3856 lines
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Entry
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- *601614 - NETRIN 1; NTN1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601614</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601614">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000065320;t=ENST00000173229" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=9423" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=601614" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000065320;t=ENST00000173229" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_004822,XM_006721595,XM_047437096" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_004822" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=601614" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=03368&isoform_id=03368_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/NTN1" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/4098197,119610438,148613884,229462906,317040170,578830095,2217314842,2462558849,2462558851" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/O95631" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=9423" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000065320;t=ENST00000173229" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=NTN1" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=NTN1" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+9423" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/NTN1" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:9423" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/9423" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr17&hgg_gene=ENST00000173229.7&hgg_start=9003087&hgg_end=9244000&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601614[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601614[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000065320" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=NTN1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=NTN1" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=NTN1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=NTN1&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA31813" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:8029" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0015773.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:105088" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/NTN1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:105088" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/9423/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=9423" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006746;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-990415-168" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:9423" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=NTN1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601614
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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NETRIN 1; NTN1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
NETRIN 1, MOUSE, HOMOLOG OF<br />
|
|
NETRIN 1-LIKE; NTN1L
|
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</span>
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NTN1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NTN1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/17/215?start=-3&limit=10&highlight=215">17p13.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:9003087-9244000&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">17:9,003,087-9,244,000</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/17/215?start=-3&limit=10&highlight=215">
|
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17p13.1
|
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</a>
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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Mirror movements 4
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/618264"> 618264 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/601614" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/601614" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
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</span>
|
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</span>
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The NTN1 gene encodes netrin-1, an extracellular secreted protein that mediates axon guidance in the spinal cord during development. It is also involved in synaptogenesis, apoptosis, cell migration, and angiogenesis (summary by <a href="#17" class="mim-tip-reference" title="Meneret, A., Franz, E. A., Trouillard, O., Oliver, T. C., Zagar, Y., Robertson, S. P., Weiniarz, Q., Gardner, R. J. M., Gallea, C., Srour, M., Depienne, C., Jasoni, C. L., and 15 others. <strong>Mutations in the netrin-1 gene cause congenital mirror movements.</strong> J. Clin. Invest. 127: 3923-3936, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28945198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28945198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28945198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI95442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28945198">Meneret et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28945198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Embryologic experiments in both vertebrates and invertebrates provide evidence that developing axons are guided to their targets in the nervous system by the combined actions of attractive and repulsive guidance cues (<a href="#30" class="mim-tip-reference" title="Tessier-Lavigne, M., Goodman, C. S. <strong>The molecular biology of axon guidance.</strong> Science 274: 1123-1133, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8895455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8895455</a>] [<a href="https://doi.org/10.1126/science.274.5290.1123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8895455">Tessier-Lavigne and Goodman, 1996</a>). One family of putative guidance cues for developing axons are the netrins, large (approximately 70-80 kD), soluble proteins that show homology in their amino termini to portions of the extracellular matrix molecule laminin (see <a href="/entry/150320">150320</a>) and that have been implicated in axon guidance through distinct and complementary lines of evidence in worms, flies, and vertebrates. Netrin-1 is a diffusible protein made by floor plate cells; it can attract spinal commissural axons and repel trochlear axons in vitro (summary by <a href="#25" class="mim-tip-reference" title="Serafini, T., Colamarino, S. A., Leonardo, E. D., Wang, H., Beddington, R., Skarnes, W. C., Tessier-Lavigne, M. <strong>Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system.</strong> Cell 87: 1001-1014, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978605</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81795-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8978605">Serafini et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8978605+8895455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#25" class="mim-tip-reference" title="Serafini, T., Colamarino, S. A., Leonardo, E. D., Wang, H., Beddington, R., Skarnes, W. C., Tessier-Lavigne, M. <strong>Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system.</strong> Cell 87: 1001-1014, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978605</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81795-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8978605">Serafini et al. (1996)</a> isolated cDNA clones comprising the entire coding region of murine netrin-1. PCR was performed on reverse-transcribed mouse brain poly(A)+ RNA using primers based upon sequence homologies between chick netrin-1 and C. elegans Unc6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8978605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using degenerate PCR primers derived from highly conserved C-terminal domains of chicken netrin-1, netrin-2 (see <a href="/entry/602349">602349</a>), and Unc6 proteins, followed by screening of a human brainstem cDNA library, <a href="#18" class="mim-tip-reference" title="Meyerhardt, J. A., Caca, K., Eckstrand, B. C., Hu, G., Lengauer, C., Banavali, S., Look, A. T., Fearon, E. R. <strong>Netrin-1: interaction with deleted in colorectal cancer (DCC) and alterations in brain tumors and neuroblastomas.</strong> Cell Growth Diff. 10: 35-42, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9950216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9950216</a>]" pmid="9950216">Meyerhardt et al. (1999)</a> isolated NTN1 cDNA. The NTN1 gene encodes a 604-amino acid protein with 98% identity to mouse netrin-1 and 50% identity to C. elegans Unc6. Northern blot analysis detected a 5.0-kb NTN1 transcript in most normal adult human tissues studied. Markedly reduced or absent NTN1 expression was seen in approximately 50% of brain tumors and neuroblastomas by RNase protection assays. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9950216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using Xenopus, <a href="#9" class="mim-tip-reference" title="Hopker, V. H., Shewan, D., Tessier-Lavigne, M., Poo, M., Holt, C. <strong>Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1.</strong> Nature 401: 69-73, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485706</a>] [<a href="https://doi.org/10.1038/43441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485706">Hopker et al. (1999)</a> demonstrated that laminin-1-beta (<a href="/entry/150240">150240</a>) from the extracellular matrix converts netrin-mediated attraction into repulsion. A soluble peptide fragment of laminin-1-beta (YIGSR) mimicked this laminin-induced conversion. Low levels of cAMP in growth cones also led to the conversion of netrin-induced attraction into repulsion, and <a href="#9" class="mim-tip-reference" title="Hopker, V. H., Shewan, D., Tessier-Lavigne, M., Poo, M., Holt, C. <strong>Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1.</strong> Nature 401: 69-73, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485706</a>] [<a href="https://doi.org/10.1038/43441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485706">Hopker et al. (1999)</a> showed that the amount of cAMP decreases in the presence of laminin-1 or YIGSR, suggesting a possible mechanism for laminin's effect. At the netrin-1-rich optic nerve head, where axons turn sharply to leave the eye, laminin-1 is confined to the retinal surface. Repulsion from the region in which laminin and netrin are coexpressed may help to drive axons into the region where only netrin is present, providing a mechanism for their escape from the retinal surface. <a href="#9" class="mim-tip-reference" title="Hopker, V. H., Shewan, D., Tessier-Lavigne, M., Poo, M., Holt, C. <strong>Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1.</strong> Nature 401: 69-73, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485706</a>] [<a href="https://doi.org/10.1038/43441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485706">Hopker et al. (1999)</a> concluded that extracellular matrix molecules not only promote axon outgrowth, but also modify the behavior of growth cones in response to diffusible guidance cues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10485706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Meyerhardt, J. A., Caca, K., Eckstrand, B. C., Hu, G., Lengauer, C., Banavali, S., Look, A. T., Fearon, E. R. <strong>Netrin-1: interaction with deleted in colorectal cancer (DCC) and alterations in brain tumors and neuroblastomas.</strong> Cell Growth Diff. 10: 35-42, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9950216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9950216</a>]" pmid="9950216">Meyerhardt et al. (1999)</a> showed that netrin-1 protein could be crosslinked to DCC (<a href="/entry/120470">120470</a>) protein on the cell surface, but did not immunoprecipitate with DCC in the absence of crosslinking and failed to bind to a soluble fusion protein containing the entire DCC extracellular domain. <a href="#18" class="mim-tip-reference" title="Meyerhardt, J. A., Caca, K., Eckstrand, B. C., Hu, G., Lengauer, C., Banavali, S., Look, A. T., Fearon, E. R. <strong>Netrin-1: interaction with deleted in colorectal cancer (DCC) and alterations in brain tumors and neuroblastomas.</strong> Cell Growth Diff. 10: 35-42, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9950216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9950216</a>]" pmid="9950216">Meyerhardt et al. (1999)</a> concluded that the binding of netrin-1 to DCC appears to depend on the presence of a coreceptor or accessory proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9950216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The axonal chemoattractant netrin-1 guides spinal commissural axons by activating its receptor DCC. <a href="#8" class="mim-tip-reference" title="Galko, M. J., Tessier-Lavigne, M. <strong>Function of an axonal chemoattractant modulated by metalloprotease activity.</strong> Science 289: 1365-1367, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10958786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10958786</a>] [<a href="https://doi.org/10.1126/science.289.5483.1365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10958786">Galko and Tessier-Lavigne (2000)</a> found that chemical inhibitors of metalloproteases potentiate netrin-mediated axon outgrowth in vitro. <a href="#8" class="mim-tip-reference" title="Galko, M. J., Tessier-Lavigne, M. <strong>Function of an axonal chemoattractant modulated by metalloprotease activity.</strong> Science 289: 1365-1367, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10958786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10958786</a>] [<a href="https://doi.org/10.1126/science.289.5483.1365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10958786">Galko and Tessier-Lavigne (2000)</a> also found that DCC is a substrate for metalloprotease-dependent ectodomain shedding, and that the inhibitors block proteolytic processing of DCC and cause an increase in DCC protein levels on axons within spinal cord explants. Thus, <a href="#8" class="mim-tip-reference" title="Galko, M. J., Tessier-Lavigne, M. <strong>Function of an axonal chemoattractant modulated by metalloprotease activity.</strong> Science 289: 1365-1367, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10958786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10958786</a>] [<a href="https://doi.org/10.1126/science.289.5483.1365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10958786">Galko and Tessier-Lavigne (2000)</a> suggested that potentiation of netrin activity by inhibitors may result from stabilization of DCC on the axons, and proteolytic activity may regulate axon migration by controlling the number of functional extracellular axon guidance receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10958786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Corset, V., Nguyen-Ba-Charvet, K. T., Forcet, C., Moyse, E., Chedotal, A., Mehlen, P. <strong>Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor.</strong> Nature 407: 747-750, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11048721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11048721</a>] [<a href="https://doi.org/10.1038/35037600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11048721">Corset et al. (2000)</a> showed that DCC interacts with the membrane-associated adenosine A2b receptor (<a href="/entry/600466">600466</a>), a G protein-coupled receptor that induces cAMP accumulation on binding adenosine. <a href="#2" class="mim-tip-reference" title="Corset, V., Nguyen-Ba-Charvet, K. T., Forcet, C., Moyse, E., Chedotal, A., Mehlen, P. <strong>Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor.</strong> Nature 407: 747-750, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11048721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11048721</a>] [<a href="https://doi.org/10.1038/35037600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11048721">Corset et al. (2000)</a> showed that adenosine A2b receptor is actually a netrin-1 receptor and induces cAMP accumulation on binding netrin-1, and that netrin-1-dependent outgrowth of dorsal spinal cord axons directly involves A2b. <a href="#2" class="mim-tip-reference" title="Corset, V., Nguyen-Ba-Charvet, K. T., Forcet, C., Moyse, E., Chedotal, A., Mehlen, P. <strong>Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor.</strong> Nature 407: 747-750, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11048721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11048721</a>] [<a href="https://doi.org/10.1038/35037600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11048721">Corset et al. (2000)</a> concluded that the growth-promoting function of netrin-1 may require a receptor complex containing DCC and A2b. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11048721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Stein, E., Zou, Y., Poo, M., Tessier-Lavigne, M. <strong>Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation.</strong> Science 291: 1976-1982, 2001. Note: Expression of Concern: Science 378: 1284 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239160</a>] [<a href="https://doi.org/10.1126/science.1059391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239160">Stein et al. (2001)</a> demonstrated that netrin-1 binds DCC and that the DCC cytoplasmic domain fused to a heterologous receptor ectodomain can mediate guidance through a mechanism involving derepression of cytoplasmic domain multimerization. Activation of the adenosine A2B receptor, proposed to contribute to netrin effects on axons, is not required for rat commissural axon outgrowth or Xenopus spinal axon attraction to netrin-1. Thus, <a href="#29" class="mim-tip-reference" title="Stein, E., Zou, Y., Poo, M., Tessier-Lavigne, M. <strong>Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation.</strong> Science 291: 1976-1982, 2001. Note: Expression of Concern: Science 378: 1284 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239160</a>] [<a href="https://doi.org/10.1126/science.1059391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239160">Stein et al. (2001)</a> concluded that DCC plays a central role in netrin signaling of axon growth and guidance independent of A2B receptor activation. Note that an expression of concern was published for the article by <a href="#29" class="mim-tip-reference" title="Stein, E., Zou, Y., Poo, M., Tessier-Lavigne, M. <strong>Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation.</strong> Science 291: 1976-1982, 2001. Note: Expression of Concern: Science 378: 1284 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239160</a>] [<a href="https://doi.org/10.1126/science.1059391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239160">Stein et al. (2001)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239160" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: they become repelled by the repellent Slit (<a href="/entry/603746">603746</a>) and simultaneously lose responsiveness to the attractant netrin. These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. <a href="#28" class="mim-tip-reference" title="Stein, E., Tessier-Lavigne, M. <strong>Hierarchical organization of guidance receptors: silencing of netrin attraction by Slit through a Robo/DCC receptor complex.</strong> Science 291: 1928-1938, 2001. Note: Expression of Concern: Science 378: 1284 only, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239147</a>] [<a href="https://doi.org/10.1126/science.1058445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239147">Stein and Tessier-Lavigne (2001)</a> provided evidence that these 2 changes are causally linked: in the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Roundabout (Robo; <a href="/entry/602430">602430</a>) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC. Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 'whole-optic pathway' preparation in Xenopus devised to assess the behavior of retinal growth cones at 4 defined points along the optic pathway, <a href="#26" class="mim-tip-reference" title="Shewan, D., Dwivedy, A., Anderson, R., Holt, C. E. <strong>Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway.</strong> Nature Neurosci. 5: 955-962, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12352982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12352982</a>] [<a href="https://doi.org/10.1038/nn919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12352982">Shewan et al. (2002)</a> found a gradual change in axonal response to netrin-1, from attraction to repulsion at progressively distal points along the pathway. Axons aged in culture underwent similar changes which correlated with a decline in cAMP and netrin-1 receptor (ADORA2B; <a href="/entry/600446">600446</a>) expression, suggesting that responsiveness is intrinsically and developmentally regulated, and also suggesting a possible molecular basis for the altered responsiveness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12352982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Forcet, C., Stein, E., Pays, L., Corset, V., Llambi, F., Tessier-Lavigne, M., Mehlen, P. <strong>Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.</strong> Nature 417: 443-447, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986622</a>] [<a href="https://doi.org/10.1038/nature748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11986622">Forcet et al. (2002)</a> showed that in embryonic kidney cells expressing full-length, but not cytoplasmic domain-truncated, DCC (<a href="/entry/120470">120470</a>), NTN1 causes increased transient phosphorylation and activity of ERK1 (<a href="/entry/601795">601795</a>) and ERK2 (<a href="/entry/176948">176948</a>), but not of JNK1 (<a href="/entry/601158">601158</a>), JNK2 (<a href="/entry/602896">602896</a>), or p38 (MAPK14; <a href="/entry/600289">600289</a>). This phosphorylation was mediated by MEK1 (MAP2K1; <a href="/entry/176872">176872</a>) and/or MEK2 (MAP2K2; <a href="/entry/601263">601263</a>). NTN1 also activated the transcription factor ELK1 (<a href="/entry/311040">311040</a>) and serum response element-regulated gene expression. Immunoprecipitation analysis showed interaction of full-length DCC with MEK1/2 in the presence or absence of NTN1. <a href="#5" class="mim-tip-reference" title="Forcet, C., Stein, E., Pays, L., Corset, V., Llambi, F., Tessier-Lavigne, M., Mehlen, P. <strong>Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.</strong> Nature 417: 443-447, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986622</a>] [<a href="https://doi.org/10.1038/nature748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11986622">Forcet et al. (2002)</a> showed that activation of Dcc by Ntn1 in rat embryonic day-13 dorsal spinal cord stimulates and is required for the outgrowth of commissural axons and Erk1/2 activation. Immunohistochemical analysis demonstrated expression of activated Erk1/2 in embryonic commissural axons, and this expression was diminished in Dcc or Ntn1 knockout animals. <a href="#5" class="mim-tip-reference" title="Forcet, C., Stein, E., Pays, L., Corset, V., Llambi, F., Tessier-Lavigne, M., Mehlen, P. <strong>Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.</strong> Nature 417: 443-447, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986622</a>] [<a href="https://doi.org/10.1038/nature748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11986622">Forcet et al. (2002)</a> concluded that the MAPK pathway is involved in responses to NTN1 and proposed that ERK activation affects axonal growth by phosphorylation of microtubule-associated proteins and neurofilaments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11986622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Ming, G., Wong, S. T., Henley, J., Yuan, X., Song, H., Spitzer, N. C., Poo, M. <strong>Adaptation in the chemotactic guidance of nerve growth cones.</strong> Nature 417: 411-418, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986620</a>] [<a href="https://doi.org/10.1038/nature745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11986620">Ming et al. (2002)</a> found that axonal growth cones of cultured frog spinal neurons exhibit adaptation during chemotactic migration, undergoing consecutive phases of desensitization and resensitization in the presence of increasing basal concentrations of the guidance factors Ntn1 or Bdnf1 (<a href="/entry/113505">113505</a>). Ntn1- or Bdnf1-specific desensitization was accompanied by a reduction of calcium signaling, whereas resensitization required activation of Mapk and local protein synthesis. <a href="#19" class="mim-tip-reference" title="Ming, G., Wong, S. T., Henley, J., Yuan, X., Song, H., Spitzer, N. C., Poo, M. <strong>Adaptation in the chemotactic guidance of nerve growth cones.</strong> Nature 417: 411-418, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986620</a>] [<a href="https://doi.org/10.1038/nature745" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11986620">Ming et al. (2002)</a> suggested that the protracted nature of this process allows adaptive changes in the sensitivity of the growth cone and that the adaptive behavior exemplifies the image of the growth cone as a chemotaking amoeba, as proposed in the 19th century by Ramon y Cajal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11986620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Nishiyama, M., Hoshino, A., Tsai, L., Henley, J. R., Goshima, Y., Tessier-Lavigne, M., Poo, M., Hong, K. <strong>Cyclic AMP/GMP-dependent modulation of Ca(2+) channels sets the polarity of nerve growth-cone turning.</strong> Nature 423: 990-995, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12827203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12827203</a>] [<a href="https://doi.org/10.1038/nature01751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12827203">Nishiyama et al. (2003)</a> reported that the ratio of cyclic AMP to cyclic GMP activities sets the polarity of netrin-1-induced axon guidance: high ratios favor attraction, whereas low ratios favor repulsion. Whole-cell recordings of calcium currents in Xenopus spinal neuron growth cones indicated that cyclic nucleotide signaling directly modulates the activity of L-type calcium channels in axonal growth cones. Furthermore, cyclic GMP signaling activated by an arachidonate 12-lipoxygenase metabolite suppressed L-type calcium channel activity triggered by netrin-1, and was required for growth cone repulsion mediated by the DCC-UNC5 (see <a href="/entry/603610">603610</a>) receptor complex. By linking cyclic AMP and cyclic GMP signaling and modulation of calcium channel activity in growth cones, these findings delineated an early membrane-associated event responsible for signal transduction during bidirectional axon guidance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12827203" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Mehlen, P., Rabizadeh, S., Snipas, S. J., Assa-Munt, N., Salvesen, G. S., Bredesen, D. E. <strong>The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis.</strong> Nature 395: 801-804, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9796814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9796814</a>] [<a href="https://doi.org/10.1038/27441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9796814">Mehlen et al. (1998)</a> showed that DCC induces apoptosis conditionally: by functioning as a dependence receptor, DCC induces apoptosis unless it is engaged by its ligand netrin-1. <a href="#15" class="mim-tip-reference" title="Mazelin, L., Bernet, A., Bonod-Bidaud, C., Pays, L., Arnaud, S., Gespach, C., Bredesen, D. E., Scoazec, J.-Y., Mehlen, P. <strong>Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.</strong> Nature 431: 80-84, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15343335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15343335</a>] [<a href="https://doi.org/10.1038/nature02788" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15343335">Mazelin et al. (2004)</a> demonstrated that inhibition of cell death by enforced expression of netrin-1 in mouse gastrointestinal tract led to the spontaneous formation of hyperplastic and neoplastic lesions. Moreover, in the adenomatous polyposis coli mutant background associated with adenoma formation, enforced expression of netrin-1 engendered aggressive adenocarcinomatous malignancies. <a href="#15" class="mim-tip-reference" title="Mazelin, L., Bernet, A., Bonod-Bidaud, C., Pays, L., Arnaud, S., Gespach, C., Bredesen, D. E., Scoazec, J.-Y., Mehlen, P. <strong>Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.</strong> Nature 431: 80-84, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15343335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15343335</a>] [<a href="https://doi.org/10.1038/nature02788" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15343335">Mazelin et al. (2004)</a> concluded that netrin-1 can promote intestinal tumor development, probably by regulating cell survival. Thus, a netrin-1 receptor or receptors function as conditional tumor suppressors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9796814+15343335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Blood vessels and nerves often follow with parallel trajectories, suggesting that distal targets use common cues that induce vascularization and innervation. Netrins are secreted by the floor plate and attract commissural axons toward the midline of the neural tube. <a href="#22" class="mim-tip-reference" title="Park, K. W., Crouse, D., Lee, M., Karnik, S. K., Sorensen, L. K., Murphy, K. J., Kuo, C. J., Li, D. Y. <strong>The axonal attractant netrin-1 is an angiogenic factor.</strong> Proc. Nat. Acad. Sci. 101: 16210-16215, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405984101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520390">Park et al. (2004)</a> showed that netrin-1 is also a potent vascular mitogen. Netrin-1 stimulates proliferation, induces migration, and promotes adhesion of endothelial cells and vascular smooth muscle cells with a specific activity comparable to vascular endothelial growth factor (PEGF; <a href="/entry/192240">192240</a>) and platelet-derived growth factor (PDGF; see <a href="/entry/173430">173430</a>). The authors presented evidence indicating that the netrin receptor neogenin (NEO1; <a href="/entry/601907">601907</a>) mediates netrin signaling in vascular smooth muscle cells, but suggested that an unidentified receptor mediates the proangiogenic effects of netrin-1 on endothelial cells. Netrin-1 also stimulates angiogenesis in vivo and augments the response to vascular endothelial growth factor. <a href="#22" class="mim-tip-reference" title="Park, K. W., Crouse, D., Lee, M., Karnik, S. K., Sorensen, L. K., Murphy, K. J., Kuo, C. J., Li, D. Y. <strong>The axonal attractant netrin-1 is an angiogenic factor.</strong> Proc. Nat. Acad. Sci. 101: 16210-16215, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405984101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520390">Park et al. (2004)</a> concluded that netrin-1 is a secreted neural guidance cue with the unique ability to attract both blood vessels and axons and that other cues may also function as vascular endothelial growth factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Netrin proteins play a role in the developing nervous system by promoting both axonal outgrowth and axonal guidance in pathfinding. <a href="#12" class="mim-tip-reference" title="Liu, G., Beggs, H., Jurgensen, C., Park, H.-T., Tang, H., Gorski, J., Jones, K. R., Reichardt, L. F., Wu, J., Rao, Y. <strong>Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction.</strong> Nature Neurosci. 7: 1222-1232, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15494732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15494732</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15494732[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nn1331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15494732">Liu et al. (2004)</a>, <a href="#11" class="mim-tip-reference" title="Li, W., Lee, J., Vikis, H. G., Lee, S.-H., Liu, G., Aurandt, J., Shen, T.-L., Fearon, E. R., Guan, J.-L., Han, M., Rao, Y., Hong, K., Guan, K.-L. <strong>Activation of FAK and Src are receptor-proximal events required for netrin signaling.</strong> Nature Neurosci. 7: 1213-1221, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15494734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15494734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15494734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nn1329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15494734">Li et al. (2004)</a>, and <a href="#24" class="mim-tip-reference" title="Ren, X., Ming, G., Xie, Y., Hong, Y., Sun, D., Zhao, Z., Feng, Z., Wang, Q., Shim, S., Chen, Z., Song, H., Mei, L., Xiong, W. <strong>Focal adhesion kinase in netrin-1 signaling.</strong> Nature Neurosci. 7: 1204-1212, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15494733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15494733</a>] [<a href="https://doi.org/10.1038/nn1330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15494733">Ren et al. (2004)</a> simultaneously reported a complex network of intracellular signaling downstream from netrin-1 involving DCC (<a href="/entry/120470">120470</a>), focal adhesion kinase (FAK; <a href="/entry/600758">600758</a>), and FYN (<a href="/entry/137025">137025</a>), a member of the SRC family kinases (see <a href="/entry/190090">190090</a>). In neurons cultured from rat cerebral cortex, <a href="#12" class="mim-tip-reference" title="Liu, G., Beggs, H., Jurgensen, C., Park, H.-T., Tang, H., Gorski, J., Jones, K. R., Reichardt, L. F., Wu, J., Rao, Y. <strong>Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction.</strong> Nature Neurosci. 7: 1222-1232, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15494732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15494732</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15494732[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nn1331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15494732">Liu et al. (2004)</a> found that netrin-1 induced tyrosine phosphorylation of FAK and FYN, and coimmunoprecipitation studies showed direct interaction of FAK and FYN with DCC. Inhibition of FYN inhibited FAK phosphorylation, and FYN mutants inhibited the attractive turning responses to netrin. Neurons lacking the FAK gene showed reduced axonal outgrowth and attractive turning responses to netrin. In cultured neurons from chick and mouse, <a href="#11" class="mim-tip-reference" title="Li, W., Lee, J., Vikis, H. G., Lee, S.-H., Liu, G., Aurandt, J., Shen, T.-L., Fearon, E. R., Guan, J.-L., Han, M., Rao, Y., Hong, K., Guan, K.-L. <strong>Activation of FAK and Src are receptor-proximal events required for netrin signaling.</strong> Nature Neurosci. 7: 1213-1221, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15494734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15494734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15494734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nn1329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15494734">Li et al. (2004)</a> found that netrin increased tyrosine phosphorylation of DCC and FAK. Coimmunoprecipitation studies showed that DCC interacted directly with FAK and SRC to form a complex and that FAK and SRC cooperated to stimulate DCC phosphorylation by SRC. <a href="#11" class="mim-tip-reference" title="Li, W., Lee, J., Vikis, H. G., Lee, S.-H., Liu, G., Aurandt, J., Shen, T.-L., Fearon, E. R., Guan, J.-L., Han, M., Rao, Y., Hong, K., Guan, K.-L. <strong>Activation of FAK and Src are receptor-proximal events required for netrin signaling.</strong> Nature Neurosci. 7: 1213-1221, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15494734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15494734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15494734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nn1329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15494734">Li et al. (2004)</a> suggested that phosphorylated DCC acts as a kinase-coupled receptor and that FAK and SRC act downstream of DCC in netrin signaling. <a href="#24" class="mim-tip-reference" title="Ren, X., Ming, G., Xie, Y., Hong, Y., Sun, D., Zhao, Z., Feng, Z., Wang, Q., Shim, S., Chen, Z., Song, H., Mei, L., Xiong, W. <strong>Focal adhesion kinase in netrin-1 signaling.</strong> Nature Neurosci. 7: 1204-1212, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15494733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15494733</a>] [<a href="https://doi.org/10.1038/nn1330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15494733">Ren et al. (2004)</a> found that inhibition of FAK phosphorylation inhibited netrin-1-induced axonal outgrowth and guidance. The authors suggested that FAK may also function as a scaffolding protein and play a role in cytoskeletal reorganization that is necessary for neurite outgrowth and turning. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15494734+15494732+15494733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Lu, X., le Noble, F., Yuan, L., Jiang, Q., de Lafarge, B., Sugiyama, D., Breant, C., Claes, F., De Smet, F., Thomas, J.-L., Autiero, M., Carmeliet, P., Tessier-Lavigne, M., Eichmann, A. <strong>The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system.</strong> Nature 432: 179-186, 2004. Note: Editorial Expression of Concern. Nature 625: E12, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15510105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15510105</a>] [<a href="https://doi.org/10.1038/nature03080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15510105">Lu et al. (2004)</a> showed that the repulsive netrin receptor UNC5B (<a href="/entry/607870">607870</a>) is expressed by endothelial tip cells of the vascular system. Disruption of the Unc5b gene in mice or of Unc5b or netrin-1A in zebrafish led to aberrant extension of endothelial tip cell filopodia, excessive vessel branching, and abnormal navigation. Netrin-1 caused endothelial filopodial retraction, but only when Unc5b was present. Thus, <a href="#13" class="mim-tip-reference" title="Lu, X., le Noble, F., Yuan, L., Jiang, Q., de Lafarge, B., Sugiyama, D., Breant, C., Claes, F., De Smet, F., Thomas, J.-L., Autiero, M., Carmeliet, P., Tessier-Lavigne, M., Eichmann, A. <strong>The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system.</strong> Nature 432: 179-186, 2004. Note: Editorial Expression of Concern. Nature 625: E12, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15510105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15510105</a>] [<a href="https://doi.org/10.1038/nature03080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15510105">Lu et al. (2004)</a> concluded that UNC5B functions as a repulsive netrin receptor in endothelial cells controlling morphogenesis of the vascular system. An Editorial Expression of Concern was published for the article by <a href="#13" class="mim-tip-reference" title="Lu, X., le Noble, F., Yuan, L., Jiang, Q., de Lafarge, B., Sugiyama, D., Breant, C., Claes, F., De Smet, F., Thomas, J.-L., Autiero, M., Carmeliet, P., Tessier-Lavigne, M., Eichmann, A. <strong>The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system.</strong> Nature 432: 179-186, 2004. Note: Editorial Expression of Concern. Nature 625: E12, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15510105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15510105</a>] [<a href="https://doi.org/10.1038/nature03080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15510105">Lu et al. (2004)</a> because image integrity issues had been raised about some of the images. The editors found that some panels of Supplementary Figure 2E appeared to have been duplicated, but noted that the authors provided contemporaneous replicates that confirmed the validity of the data presented in the figure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15510105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Larrivee, B., Freitas, C., Trombe, M., Lv, X., DeLafarge, B., Yuan, L., Bouvree, K., Breant, C., Del Toro, R., Brechot, N., Germain, S., Bono, F., Dol, F., Claes, F., Fischer, C., Autiero, M., Thomas, J.-L., Carmeliet, P., Tessier-Lavigne, M., Eichmann, A. <strong>Activation of the UNC5B receptor by netrin-1 inhibits sprouting angiogenesis.</strong> Genes Dev. 21: 2433-2447, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17908930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17908930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17908930[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.437807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17908930">Larrivee et al. (2007)</a> found that Unc5b was downregulated in quiescent adult mouse vasculature, but it was reexpressed during sprouting angiogenesis in 3-dimensional gels and in tumor implants. Stimulation of Unc5b-expressing neovessels with netrin-1 inhibited sprouting angiogenesis, and genetic loss of Unc5b reduced netrin-1-mediated inhibition of angiogenesis. Expression of Unc5b triggered endothelial cell repulsion in response to netrin-1 in vitro, whereas a truncated Unc5b lacking the intracellular signaling domain failed to induce repulsion. <a href="#10" class="mim-tip-reference" title="Larrivee, B., Freitas, C., Trombe, M., Lv, X., DeLafarge, B., Yuan, L., Bouvree, K., Breant, C., Del Toro, R., Brechot, N., Germain, S., Bono, F., Dol, F., Claes, F., Fischer, C., Autiero, M., Thomas, J.-L., Carmeliet, P., Tessier-Lavigne, M., Eichmann, A. <strong>Activation of the UNC5B receptor by netrin-1 inhibits sprouting angiogenesis.</strong> Genes Dev. 21: 2433-2447, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17908930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17908930</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17908930[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.437807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17908930">Larrivee et al. (2007)</a> concluded that activation of UNC5B by netrin-1 inhibits sprouting angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17908930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Wang, G. X., Poo, M. <strong>Requirement of TRPC channels in netrin-1-induced chemotropic turning of nerve growth cones.</strong> Nature 434: 898-904, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15758951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15758951</a>] [<a href="https://doi.org/10.1038/nature03478" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15758951">Wang and Poo (2005)</a> reported that TRP (transient receptor potential)-like channel activity exists in the growth cones of cultured Xenopus neurons and can be modulated by exposure to netrin-1 and brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>), 2 chemoattractants for axon guidance. Whole-cell recording from growth cones showed that netrin-1 induced a membrane depolarization, part of which remained after all major voltage-dependent channels were blocked. Furthermore, the membrane depolarization was sensitive to blockers of TRP channels. Pharmacologic blockade of putative TRP currents or downregulation of Xenopus TRP1 (xTRPC1) expression with a specific morpholino oligonucleotide abolished the growth cone turning and calcium ion elevation induced by a netrin-1 gradient. Thus, <a href="#31" class="mim-tip-reference" title="Wang, G. X., Poo, M. <strong>Requirement of TRPC channels in netrin-1-induced chemotropic turning of nerve growth cones.</strong> Nature 434: 898-904, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15758951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15758951</a>] [<a href="https://doi.org/10.1038/nature03478" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15758951">Wang and Poo (2005)</a> concluded that TRPC currents reflect early events in the growth cone's detection of some extracellular guidance signal, resulting in membrane depolarization and cytoplasmic calcium ion elevation that mediates the turning of growth cones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15758951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Wilson, B. D., Li, M., Park, K. W., Suli, A., Sorensen, L. K., Larrieu-Lahargue, F., Urness, L. D., Suh, W., Asai, J., Kock, G. A. H., Thorne, T., Silver, M., Thomas, K. R., Chien, C.-B., Losordo, D. W., Li, D. Y. <strong>Netrins promote developmental and therapeutic angiogenesis.</strong> Science 313: 640-644, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16809490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16809490</a>] [<a href="https://doi.org/10.1126/science.1124704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16809490">Wilson et al. (2006)</a> demonstrated that netrins stimulate proliferation, migration, and tube formation of human endothelial cells in vitro and that this stimulation is independent of known netrin receptors. Suppression of netrin-1a mRNA in zebrafish inhibited vascular sprouting, implying a proangiogenic role for netrins during vertebrate development. <a href="#32" class="mim-tip-reference" title="Wilson, B. D., Li, M., Park, K. W., Suli, A., Sorensen, L. K., Larrieu-Lahargue, F., Urness, L. D., Suh, W., Asai, J., Kock, G. A. H., Thorne, T., Silver, M., Thomas, K. R., Chien, C.-B., Losordo, D. W., Li, D. Y. <strong>Netrins promote developmental and therapeutic angiogenesis.</strong> Science 313: 640-644, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16809490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16809490</a>] [<a href="https://doi.org/10.1126/science.1124704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16809490">Wilson et al. (2006)</a> also showed that netrins accelerate neovascularization in an in vivo model of ischemia and that they reverse neuropathy and vasculopathy in a diabetic murine model. <a href="#32" class="mim-tip-reference" title="Wilson, B. D., Li, M., Park, K. W., Suli, A., Sorensen, L. K., Larrieu-Lahargue, F., Urness, L. D., Suh, W., Asai, J., Kock, G. A. H., Thorne, T., Silver, M., Thomas, K. R., Chien, C.-B., Losordo, D. W., Li, D. Y. <strong>Netrins promote developmental and therapeutic angiogenesis.</strong> Science 313: 640-644, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16809490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16809490</a>] [<a href="https://doi.org/10.1126/science.1124704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16809490">Wilson et al. (2006)</a> found that vectors expressing netrin-1 and netrin-4 (NTN4; <a href="/entry/610401">610401</a>) are comparable in effectiveness to vectors expressing VEGF (<a href="/entry/192240">192240</a>) and promoting neovascularization and reperfusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16809490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Colon-Ramos, D. A., Margeta, M. A., Shen, K. <strong>Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans.</strong> Science 318: 103-106, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17916735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17916735</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17916735[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1143762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17916735">Colon-Ramos et al. (2007)</a> showed that connectivity between 2 interneurons in C. elegans, AIY and RIA, is orchestrated by a pair of glial cells that express UNC6 (netrin-1). In the postsynaptic neuron RIA, the netrin receptor UNC40 (DCC; <a href="/entry/120470">120470</a>) plays a conventional guidance role, directing outgrowth of the RIA process ventrally toward the glia. The authors demonstrated that in the presynaptic neuron AIY, UNC40 plays an unexpected and theretofore uncharacterized role: it cell-autonomously promotes assembly of presynaptic terminals in the immediate vicinity of the glial cell endfeet. <a href="#1" class="mim-tip-reference" title="Colon-Ramos, D. A., Margeta, M. A., Shen, K. <strong>Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans.</strong> Science 318: 103-106, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17916735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17916735</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17916735[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1143762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17916735">Colon-Ramos et al. (2007)</a> concluded that netrin can be used both for guidance and local synaptogenesis and suggested that glial cells can function as guideposts during the assembly of neural circuits in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17916735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using cultured rat and frog spinal neurons, <a href="#14" class="mim-tip-reference" title="Ly, A., Nikolaev, A., Suresh, G., Zheng, Y., Tessier-Lavigne, M., Stein, E. <strong>DSCAM is a netrin receptor that collaborates with DCC in mediating turning responses to netrin-1.</strong> Cell 133: 1241-1254, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18585357/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18585357</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18585357[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2008.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18585357">Ly et al. (2008)</a> showed that Dscam (<a href="/entry/602523">602523</a>) could mediate the turning response to netrin-1 both alone and in collaboration with the netrin receptor Dcc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18585357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using primary neurons derived from rat, mouse, and chicken embryos, <a href="#7" class="mim-tip-reference" title="Furne, C., Rama, N., Corset, V., Chedotal, A., Mehlen, P. <strong>Netrin-1 is a survival factor during commissural neuron navigation.</strong> Proc. Nat. Acad. Sci. 105: 14465-14470, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18796601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18796601</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18796601[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0803645105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18796601">Furne et al. (2008)</a> showed that Ntn1, in addition to behaving as an attractive cue, functioned in cell survival by inhibiting the proapoptotic activity of Dcc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18796601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By quantitative RT-PCR of 51 primary breast tumors, <a href="#4" class="mim-tip-reference" title="Fitamant, J., Guenebeaud, C., Coissieux, M.-M., Guix, C., Treilleux, I., Scoazec, J.-Y., Bachelot, T., Bernet, A., Mehlen, P. <strong>Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer.</strong> Proc. Nat. Acad. Sci. 105: 4850-4855, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18353983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18353983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18353983[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709810105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18353983">Fitamant et al. (2008)</a> found significantly increased expression of netrin-1 in a high proportion of lymph node-positive tumors and tumors from metastatic patients. Netrin-1-expressing mammary metastatic tumor cell lines underwent apoptosis when netrin-1 expression was experimentally decreased or when decoy soluble netrin receptor ectodomains were added. Such treatments prevented lung metastasis of a mammary cancer cell line and a xenografted human breast tumor in mice. <a href="#4" class="mim-tip-reference" title="Fitamant, J., Guenebeaud, C., Coissieux, M.-M., Guix, C., Treilleux, I., Scoazec, J.-Y., Bachelot, T., Bernet, A., Mehlen, P. <strong>Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer.</strong> Proc. Nat. Acad. Sci. 105: 4850-4855, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18353983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18353983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18353983[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709810105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18353983">Fitamant et al. (2008)</a> concluded that netrin-1 expression confers a selective advantage for tumor cell survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18353983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Moore, S. W., Biais, N., Sheetz, M. P. <strong>Traction on immobilized netrin-1 is sufficient to reorient axons.</strong> Science 325: 166 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19589994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19589994</a>] [<a href="https://doi.org/10.1126/science.1173851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19589994">Moore et al. (2009)</a> showed that traction on immobilized netrin-1 was sufficient to reorient axons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19589994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Delloye-Bourgeois, C., Fitamant, J., Paradisi, A., Cappellen, D., Douc-Rasy, S., Raquin, M.-A., Stupack, D., Nakagawara, A., Rousseau, R., Combaret, V., Puisieux, A., Valteau-Couanet, D., Benard, J., Bernet, A., Mehlen, P. <strong>Netrin-1 acts as a survival factor for aggressive neuroblastoma.</strong> J. Exp. Med. 206: 833-847, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19349462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19349462</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19349462[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20082299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19349462">Delloye-Bourgeois et al. (2009)</a> showed that autocrine production of NTN1 conveyed a selective advantage in tumor growth and dissemination in aggressive forms of neuroblastoma (NB; see <a href="/entry/256700">256700</a>) by blocking the proapoptotic activity of the UNC5H receptors. NTN1 upregulation appeared to be a marker for poor prognosis in infants with stage 4S and stage 4 NB. NTN1 disruption blocked NB metastasis in animals, and <a href="#3" class="mim-tip-reference" title="Delloye-Bourgeois, C., Fitamant, J., Paradisi, A., Cappellen, D., Douc-Rasy, S., Raquin, M.-A., Stupack, D., Nakagawara, A., Rousseau, R., Combaret, V., Puisieux, A., Valteau-Couanet, D., Benard, J., Bernet, A., Mehlen, P. <strong>Netrin-1 acts as a survival factor for aggressive neuroblastoma.</strong> J. Exp. Med. 206: 833-847, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19349462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19349462</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19349462[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20082299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19349462">Delloye-Bourgeois et al. (2009)</a> proposed disrupting NTN1 expression as an anticancer strategy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19349462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#33" class="mim-tip-reference" title="Xu, K., Wu, Z., Renier, N., Antipenko, A., Tzvetkova-Robev, D., Xu, Y., Minchenko, M., Nardi-Dei, V., Rajashankar, K. R., Himanen, J., Tessier-Lavigne, M., Nikolov, D. B. <strong>Structures of netrin-1 bound to two receptors provide insight into its axon guidance mechanism.</strong> Science 344: 1275-1279, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24876346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24876346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24876346[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1255149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24876346">Xu et al. (2014)</a> determined the structures of a functional NTN1 region, alone and in complexes with NEO1 (<a href="/entry/601907">601907</a>) and DCC (<a href="/entry/120470">120470</a>). NTN1 has a rigid elongated structure containing 2 receptor-binding sites at opposite ends through which it brings together receptor molecules. The ligand/receptor complexes reveal 2 distinct architectures: a 2:2 heterotetramer and a continuous ligand/receptor assembly. The differences result from different lengths of the linker connecting receptor domains fibronectin type III domain 4 (FN4) and FN5, which differs among DCC and NEO1 splice variants, providing a basis for diverse signaling outcomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24876346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#18" class="mim-tip-reference" title="Meyerhardt, J. A., Caca, K., Eckstrand, B. C., Hu, G., Lengauer, C., Banavali, S., Look, A. T., Fearon, E. R. <strong>Netrin-1: interaction with deleted in colorectal cancer (DCC) and alterations in brain tumors and neuroblastomas.</strong> Cell Growth Diff. 10: 35-42, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9950216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9950216</a>]" pmid="9950216">Meyerhardt et al. (1999)</a> mapped the human NTN1 gene to chromosome 17p13-p12 by FISH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9950216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In members of 2 unrelated families and in an unrelated patient with mirror movements-4 (MRMV4; <a href="/entry/618264">618264</a>), <a href="#17" class="mim-tip-reference" title="Meneret, A., Franz, E. A., Trouillard, O., Oliver, T. C., Zagar, Y., Robertson, S. P., Weiniarz, Q., Gardner, R. J. M., Gallea, C., Srour, M., Depienne, C., Jasoni, C. L., and 15 others. <strong>Mutations in the netrin-1 gene cause congenital mirror movements.</strong> J. Clin. Invest. 127: 3923-3936, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28945198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28945198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28945198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI95442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28945198">Meneret et al. (2017)</a> identified heterozygous mutations in the NTN1 gene (<a href="#0001">601614.0001</a>-<a href="#0003">601614.0003</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the condition in the 2 families; the patient in the third family had sporadic occurrence and the mutation occurred de novo. All mutations occurred in the NTR domain and were predicted to affect protein structure and/or stability. In vitro functional expression studies in HeLa and HEK293 cells showed that unlike wildtype, the mutant proteins were almost exclusively found in the intracellular compartments and could not be detected in the supernatant. Since netrin-1 is a diffusible extracellular cue, the pathophysiology probably involved a loss of function. The patients were ascertained from a cohort of 47 index cases with congenital mirror movements in whom mutations in other MRMV-associated genes were excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28945198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#25" class="mim-tip-reference" title="Serafini, T., Colamarino, S. A., Leonardo, E. D., Wang, H., Beddington, R., Skarnes, W. C., Tessier-Lavigne, M. <strong>Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system.</strong> Cell 87: 1001-1014, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978605</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81795-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8978605">Serafini et al. (1996)</a> used the method of <a href="#27" class="mim-tip-reference" title="Skarnes, W. C., Moss, J. E., Hurtley, S. M., Beddington, R. S. P. <strong>Capturing genes encoding membrane and secreted proteins important for mouse development.</strong> Proc. Nat. Acad. Sci. 92: 6592-6596, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604039</a>] [<a href="https://doi.org/10.1073/pnas.92.14.6592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604039">Skarnes et al. (1995)</a> in embryonic stem cells to selectively recover mutations in genes encoding proteins with signal sequences by virtue of creating fusions of N-terminal portions of these proteins with an exogenous transmembrane domain. In this way <a href="#25" class="mim-tip-reference" title="Serafini, T., Colamarino, S. A., Leonardo, E. D., Wang, H., Beddington, R., Skarnes, W. C., Tessier-Lavigne, M. <strong>Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system.</strong> Cell 87: 1001-1014, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978605</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81795-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8978605">Serafini et al. (1996)</a> isolated a mutated murine netrin-1 gene and transmitted it through the germline. Homozygotes were born but apparently did not suckle and died within a few days. Netrin-1-deficient mice exhibited defects in spinal commissural axon projections that were considered consistent with netrin-1 guiding these axons. Defects in several forebrain commissures were also observed, suggesting additional guidance roles for netrin-1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8978605+7604039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Poon, V. Y., Klassen, M. P., Shen, K. <strong>UNC-6/netrin and its receptor UNC-5 locally exclude presynaptic components from dendrites.</strong> Nature 455: 669-673, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18776887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18776887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18776887[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18776887">Poon et al. (2008)</a> demonstrated that the axon guidance cue unc6/netrin and its receptor unc5 (<a href="/entry/607869">607869</a>) act throughout development to exclude synaptic vesicle and active zone proteins from the dendrite of the C. elegans motor neuron DA9, which is proximal to a source of unc6/netrin. In unc6/netrin and unc5 loss-of-function mutants, presynaptic components mislocalized to the DA9 dendrite. In addition, ectopically expressed unc6/netrin, acting through unc5, was sufficient to exclude endogenous synapses from adjacent subcellular domains within the DA9 axon. Furthermore, this antisynaptogenic activity was interchangeable with that of lin44/Wnt despite being transduced through different receptors, suggesting that extracellular cues such as netrin and Wnts not only guide axon navigation but also regulate the polarized accumulation of presynaptic components through local exclusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18776887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 affected members of a French family (family 1) with mirror movements-4 (MRMV4; <a href="/entry/618264">618264</a>), <a href="#17" class="mim-tip-reference" title="Meneret, A., Franz, E. A., Trouillard, O., Oliver, T. C., Zagar, Y., Robertson, S. P., Weiniarz, Q., Gardner, R. J. M., Gallea, C., Srour, M., Depienne, C., Jasoni, C. L., and 15 others. <strong>Mutations in the netrin-1 gene cause congenital mirror movements.</strong> J. Clin. Invest. 127: 3923-3936, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28945198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28945198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28945198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI95442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28945198">Meneret et al. (2017)</a> identified a heterozygous c.1801T-C transition (c.1801T-C, NM_004822) in exon 3 of the NTN1 gene, resulting in a cys601-to-arg (C601R) substitution at a highly conserved residue in the netrin domain. The mutation, which was found by exome sequencing, was not found in the ExAC database. There were 2 asymptomatic mutation carriers, indicating incomplete penetrance. In vitro functional expression studies in HeLa and HEK293 cells showed that unlike wildtype, the mutant protein was almost exclusively found in the intracellular compartments and could not be detected in the supernatant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28945198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 MIRROR MOVEMENTS 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1567749982 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567749982;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1567749982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1567749982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000735955" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000735955" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000735955</a>
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<p>In 3 affected members of a family (family 2) with mirror movements-4 (MRMV4; <a href="/entry/618264">618264</a>), <a href="#17" class="mim-tip-reference" title="Meneret, A., Franz, E. A., Trouillard, O., Oliver, T. C., Zagar, Y., Robertson, S. P., Weiniarz, Q., Gardner, R. J. M., Gallea, C., Srour, M., Depienne, C., Jasoni, C. L., and 15 others. <strong>Mutations in the netrin-1 gene cause congenital mirror movements.</strong> J. Clin. Invest. 127: 3923-3936, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28945198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28945198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28945198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI95442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28945198">Meneret et al. (2017)</a> identified a heterozygous 3-bp deletion (c.1552_1554del, NM_004822) in exon 3 of the NTN1 gene, resulting in the deletion of conserved residue ile518 (Ile518del) in the netrin domain. The mutation, which was found by exome sequencing, was not found in the ExAC database. In vitro functional expression studies in HeLa and HEK293 cells showed that unlike wildtype, the mutant protein was almost exclusively found in the intracellular compartments and could not be detected in the supernatant. This family was previously reported as family C in <a href="#6" class="mim-tip-reference" title="Franz, E. A., Chiaroni-Clarke, R., Woodrow, S., Glendining, K. A., Jasoni, C. L., Robertson, S. P., Gardner, R. J. M., Markie, D. <strong>Congenital mirror movements: phenotypes associated with DCC and RAD51 mutations.</strong> J. Neurol. Sci. 351: 140-145, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25813273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25813273</a>] [<a href="https://doi.org/10.1016/j.jns.2015.03.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25813273">Franz et al. (2015)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28945198+25813273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0003 MIRROR MOVEMENTS 4</strong>
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NTN1, CYS601SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1567750187 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567750187;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1567750187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1567750187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000735956" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000735956" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000735956</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (family 3) with sporadic occurrence of mirror movements-4 (MRMV4; <a href="/entry/618264">618264</a>), <a href="#17" class="mim-tip-reference" title="Meneret, A., Franz, E. A., Trouillard, O., Oliver, T. C., Zagar, Y., Robertson, S. P., Weiniarz, Q., Gardner, R. J. M., Gallea, C., Srour, M., Depienne, C., Jasoni, C. L., and 15 others. <strong>Mutations in the netrin-1 gene cause congenital mirror movements.</strong> J. Clin. Invest. 127: 3923-3936, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28945198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28945198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28945198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI95442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28945198">Meneret et al. (2017)</a> identified a heterozygous c.1802G-C transversion (c.1802G-C, NM_004822) in exon 3 of the NTN1 gene, resulting in a cys601-to-ser (C601S) substitution at a highly conserved residue in the netrin domain. The mutation, which was found by exome sequencing, was not found in the ExAC database. In vitro functional expression studies in HeLa and HEK293 cells showed that unlike wildtype, the mutant protein was almost exclusively found in the intracellular compartments and could not be detected in the supernatant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28945198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<a id="references"class="mim-anchor"></a>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<ol>
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<a id="1" class="mim-anchor"></a>
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<a id="Colon-Ramos2007" class="mim-anchor"></a>
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<div class="">
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Colon-Ramos, D. A., Margeta, M. A., Shen, K.
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<strong>Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans.</strong>
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Science 318: 103-106, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17916735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17916735</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17916735[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17916735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1143762" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="Corset2000" class="mim-anchor"></a>
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Corset, V., Nguyen-Ba-Charvet, K. T., Forcet, C., Moyse, E., Chedotal, A., Mehlen, P.
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<strong>Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor.</strong>
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Nature 407: 747-750, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11048721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11048721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11048721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/35037600" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Delloye-Bourgeois2009" class="mim-anchor"></a>
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<div class="">
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Delloye-Bourgeois, C., Fitamant, J., Paradisi, A., Cappellen, D., Douc-Rasy, S., Raquin, M.-A., Stupack, D., Nakagawara, A., Rousseau, R., Combaret, V., Puisieux, A., Valteau-Couanet, D., Benard, J., Bernet, A., Mehlen, P.
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<strong>Netrin-1 acts as a survival factor for aggressive neuroblastoma.</strong>
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J. Exp. Med. 206: 833-847, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19349462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19349462</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19349462[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19349462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1084/jem.20082299" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Fitamant2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Fitamant, J., Guenebeaud, C., Coissieux, M.-M., Guix, C., Treilleux, I., Scoazec, J.-Y., Bachelot, T., Bernet, A., Mehlen, P.
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<strong>Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer.</strong>
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Proc. Nat. Acad. Sci. 105: 4850-4855, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18353983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18353983</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18353983[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18353983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0709810105" target="_blank">Full Text</a>]
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<a id="Forcet2002" class="mim-anchor"></a>
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<p class="mim-text-font">
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Forcet, C., Stein, E., Pays, L., Corset, V., Llambi, F., Tessier-Lavigne, M., Mehlen, P.
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<strong>Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.</strong>
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Nature 417: 443-447, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11986622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11986622</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11986622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature748" target="_blank">Full Text</a>]
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<a id="Franz2015" class="mim-anchor"></a>
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Franz, E. A., Chiaroni-Clarke, R., Woodrow, S., Glendining, K. A., Jasoni, C. L., Robertson, S. P., Gardner, R. J. M., Markie, D.
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<strong>Congenital mirror movements: phenotypes associated with DCC and RAD51 mutations.</strong>
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J. Neurol. Sci. 351: 140-145, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25813273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25813273</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25813273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jns.2015.03.006" target="_blank">Full Text</a>]
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<a id="Furne2008" class="mim-anchor"></a>
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Furne, C., Rama, N., Corset, V., Chedotal, A., Mehlen, P.
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<strong>Netrin-1 is a survival factor during commissural neuron navigation.</strong>
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Proc. Nat. Acad. Sci. 105: 14465-14470, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18796601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18796601</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18796601[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18796601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0803645105" target="_blank">Full Text</a>]
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<a id="Galko2000" class="mim-anchor"></a>
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<div class="">
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Galko, M. J., Tessier-Lavigne, M.
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<strong>Function of an axonal chemoattractant modulated by metalloprotease activity.</strong>
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Science 289: 1365-1367, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10958786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10958786</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10958786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.289.5483.1365" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Hopker1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Hopker, V. H., Shewan, D., Tessier-Lavigne, M., Poo, M., Holt, C.
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<strong>Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1.</strong>
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Nature 401: 69-73, 1999.
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|
|
<strong>Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system.</strong>
|
|
Cell 87: 1001-1014, 1996.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978605</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8978605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81795-x" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Shewan2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shewan, D., Dwivedy, A., Anderson, R., Holt, C. E.
|
|
<strong>Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway.</strong>
|
|
Nature Neurosci. 5: 955-962, 2002.
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|
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12352982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12352982</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12352982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nn919" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Skarnes1995" class="mim-anchor"></a>
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<div class="">
|
|
<p class="mim-text-font">
|
|
Skarnes, W. C., Moss, J. E., Hurtley, S. M., Beddington, R. S. P.
|
|
<strong>Capturing genes encoding membrane and secreted proteins important for mouse development.</strong>
|
|
Proc. Nat. Acad. Sci. 92: 6592-6596, 1995.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604039</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7604039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.92.14.6592" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Stein2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Stein, E., Tessier-Lavigne, M.
|
|
<strong>Hierarchical organization of guidance receptors: silencing of netrin attraction by Slit through a Robo/DCC receptor complex.</strong>
|
|
Science 291: 1928-1938, 2001. Note: Expression of Concern: Science 378: 1284 only, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239147</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1058445" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="29" class="mim-anchor"></a>
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<a id="Stein2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stein, E., Zou, Y., Poo, M., Tessier-Lavigne, M.
|
|
<strong>Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation.</strong>
|
|
Science 291: 1976-1982, 2001. Note: Expression of Concern: Science 378: 1284 only, 2022.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239160</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239160" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1059391" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Tessier-Lavigne1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tessier-Lavigne, M., Goodman, C. S.
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<strong>The molecular biology of axon guidance.</strong>
|
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Science 274: 1123-1133, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8895455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8895455</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8895455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.274.5290.1123" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Wang2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, G. X., Poo, M.
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<strong>Requirement of TRPC channels in netrin-1-induced chemotropic turning of nerve growth cones.</strong>
|
|
Nature 434: 898-904, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15758951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15758951</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15758951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature03478" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Wilson2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilson, B. D., Li, M., Park, K. W., Suli, A., Sorensen, L. K., Larrieu-Lahargue, F., Urness, L. D., Suh, W., Asai, J., Kock, G. A. H., Thorne, T., Silver, M., Thomas, K. R., Chien, C.-B., Losordo, D. W., Li, D. Y.
|
|
<strong>Netrins promote developmental and therapeutic angiogenesis.</strong>
|
|
Science 313: 640-644, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16809490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16809490</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16809490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1124704" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Xu2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, K., Wu, Z., Renier, N., Antipenko, A., Tzvetkova-Robev, D., Xu, Y., Minchenko, M., Nardi-Dei, V., Rajashankar, K. R., Himanen, J., Tessier-Lavigne, M., Nikolov, D. B.
|
|
<strong>Structures of netrin-1 bound to two receptors provide insight into its axon guidance mechanism.</strong>
|
|
Science 344: 1275-1279, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24876346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24876346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24876346[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24876346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1255149" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 01/02/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
|
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Ada Hamosh - updated : 7/7/2014<br>Paul J. Converse - updated : 11/12/2009<br>Patricia A. Hartz - updated : 8/31/2009<br>Ada Hamosh - updated : 8/14/2009<br>Ada Hamosh - updated : 11/5/2008<br>Patricia A. Hartz - updated : 9/10/2008<br>Patricia A. Hartz - updated : 8/13/2008<br>Patricia A. Hartz - updated : 11/2/2007<br>Ada Hamosh - updated : 10/26/2007<br>Ada Hamosh - updated : 6/27/2007<br>Anne M. Stumpf - updated : 9/8/2006<br>Ada Hamosh - updated : 9/6/2006<br>Ada Hamosh - updated : 9/19/2005<br>Cassandra L. Kniffin - updated : 2/8/2005<br>Victor A. McKusick - updated : 12/30/2004<br>Ada Hamosh - updated : 11/10/2004<br>Ada Hamosh - updated : 7/8/2003<br>Cassandra L. Kniffin - updated : 9/30/2002<br>Paul J. Converse - updated : 5/6/2002<br>Ada Hamosh - updated : 3/27/2001<br>Ada Hamosh - updated : 3/27/2001<br>Ada Hamosh - updated : 10/18/2000<br>Ada Hamosh - updated : 9/5/2000<br>Ada Hamosh - updated : 2/14/2000
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/8/1997
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</span>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/16/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/15/2024<br>carol : 01/26/2024<br>carol : 01/21/2023<br>carol : 01/09/2019<br>carol : 01/08/2019<br>ckniffin : 01/02/2019<br>carol : 04/24/2018<br>alopez : 07/07/2014<br>alopez : 7/7/2014<br>carol : 6/20/2012<br>terry : 1/20/2010<br>mgross : 11/17/2009<br>terry : 11/12/2009<br>mgross : 9/4/2009<br>terry : 8/31/2009<br>alopez : 8/18/2009<br>terry : 8/14/2009<br>alopez : 11/18/2008<br>alopez : 11/18/2008<br>terry : 11/5/2008<br>mgross : 9/12/2008<br>terry : 9/10/2008<br>mgross : 8/13/2008<br>mgross : 11/2/2007<br>terry : 11/2/2007<br>alopez : 11/1/2007<br>alopez : 11/1/2007<br>terry : 10/26/2007<br>alopez : 7/5/2007<br>terry : 6/27/2007<br>wwang : 9/13/2006<br>alopez : 9/13/2006<br>alopez : 9/8/2006<br>alopez : 9/8/2006<br>terry : 9/6/2006<br>alopez : 9/20/2005<br>terry : 9/19/2005<br>wwang : 2/17/2005<br>ckniffin : 2/8/2005<br>tkritzer : 1/21/2005<br>terry : 12/30/2004<br>tkritzer : 11/10/2004<br>mgross : 7/14/2003<br>terry : 7/8/2003<br>tkritzer : 6/19/2003<br>alopez : 11/4/2002<br>carol : 10/21/2002<br>ckniffin : 9/30/2002<br>alopez : 6/6/2002<br>mgross : 5/6/2002<br>alopez : 3/27/2001<br>alopez : 3/27/2001<br>alopez : 10/18/2000<br>alopez : 9/5/2000<br>alopez : 2/14/2000<br>alopez : 4/30/1999<br>alopez : 6/22/1998<br>alopez : 6/22/1998<br>jamie : 1/17/1997<br>mark : 1/16/1997<br>jamie : 1/15/1997<br>jamie : 1/9/1997<br>jamie : 1/9/1997<br>mark : 1/8/1997
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</span>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601614
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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NETRIN 1; NTN1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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NETRIN 1, MOUSE, HOMOLOG OF<br />
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NETRIN 1-LIKE; NTN1L
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</span>
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</h4>
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</div>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NTN1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 17p13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:9,003,087-9,244,000 </span>
|
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
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<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
17p13.1
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<td>
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<span class="mim-font">
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Mirror movements 4
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</span>
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</td>
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<td>
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<span class="mim-font">
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618264
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The NTN1 gene encodes netrin-1, an extracellular secreted protein that mediates axon guidance in the spinal cord during development. It is also involved in synaptogenesis, apoptosis, cell migration, and angiogenesis (summary by Meneret et al., 2017). </p><p>Embryologic experiments in both vertebrates and invertebrates provide evidence that developing axons are guided to their targets in the nervous system by the combined actions of attractive and repulsive guidance cues (Tessier-Lavigne and Goodman, 1996). One family of putative guidance cues for developing axons are the netrins, large (approximately 70-80 kD), soluble proteins that show homology in their amino termini to portions of the extracellular matrix molecule laminin (see 150320) and that have been implicated in axon guidance through distinct and complementary lines of evidence in worms, flies, and vertebrates. Netrin-1 is a diffusible protein made by floor plate cells; it can attract spinal commissural axons and repel trochlear axons in vitro (summary by Serafini et al., 1996). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>Serafini et al. (1996) isolated cDNA clones comprising the entire coding region of murine netrin-1. PCR was performed on reverse-transcribed mouse brain poly(A)+ RNA using primers based upon sequence homologies between chick netrin-1 and C. elegans Unc6. </p><p>Using degenerate PCR primers derived from highly conserved C-terminal domains of chicken netrin-1, netrin-2 (see 602349), and Unc6 proteins, followed by screening of a human brainstem cDNA library, Meyerhardt et al. (1999) isolated NTN1 cDNA. The NTN1 gene encodes a 604-amino acid protein with 98% identity to mouse netrin-1 and 50% identity to C. elegans Unc6. Northern blot analysis detected a 5.0-kb NTN1 transcript in most normal adult human tissues studied. Markedly reduced or absent NTN1 expression was seen in approximately 50% of brain tumors and neuroblastomas by RNase protection assays. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<p>Using Xenopus, Hopker et al. (1999) demonstrated that laminin-1-beta (150240) from the extracellular matrix converts netrin-mediated attraction into repulsion. A soluble peptide fragment of laminin-1-beta (YIGSR) mimicked this laminin-induced conversion. Low levels of cAMP in growth cones also led to the conversion of netrin-induced attraction into repulsion, and Hopker et al. (1999) showed that the amount of cAMP decreases in the presence of laminin-1 or YIGSR, suggesting a possible mechanism for laminin's effect. At the netrin-1-rich optic nerve head, where axons turn sharply to leave the eye, laminin-1 is confined to the retinal surface. Repulsion from the region in which laminin and netrin are coexpressed may help to drive axons into the region where only netrin is present, providing a mechanism for their escape from the retinal surface. Hopker et al. (1999) concluded that extracellular matrix molecules not only promote axon outgrowth, but also modify the behavior of growth cones in response to diffusible guidance cues. </p><p>Meyerhardt et al. (1999) showed that netrin-1 protein could be crosslinked to DCC (120470) protein on the cell surface, but did not immunoprecipitate with DCC in the absence of crosslinking and failed to bind to a soluble fusion protein containing the entire DCC extracellular domain. Meyerhardt et al. (1999) concluded that the binding of netrin-1 to DCC appears to depend on the presence of a coreceptor or accessory proteins. </p><p>The axonal chemoattractant netrin-1 guides spinal commissural axons by activating its receptor DCC. Galko and Tessier-Lavigne (2000) found that chemical inhibitors of metalloproteases potentiate netrin-mediated axon outgrowth in vitro. Galko and Tessier-Lavigne (2000) also found that DCC is a substrate for metalloprotease-dependent ectodomain shedding, and that the inhibitors block proteolytic processing of DCC and cause an increase in DCC protein levels on axons within spinal cord explants. Thus, Galko and Tessier-Lavigne (2000) suggested that potentiation of netrin activity by inhibitors may result from stabilization of DCC on the axons, and proteolytic activity may regulate axon migration by controlling the number of functional extracellular axon guidance receptors. </p><p>Corset et al. (2000) showed that DCC interacts with the membrane-associated adenosine A2b receptor (600466), a G protein-coupled receptor that induces cAMP accumulation on binding adenosine. Corset et al. (2000) showed that adenosine A2b receptor is actually a netrin-1 receptor and induces cAMP accumulation on binding netrin-1, and that netrin-1-dependent outgrowth of dorsal spinal cord axons directly involves A2b. Corset et al. (2000) concluded that the growth-promoting function of netrin-1 may require a receptor complex containing DCC and A2b. </p><p>Stein et al. (2001) demonstrated that netrin-1 binds DCC and that the DCC cytoplasmic domain fused to a heterologous receptor ectodomain can mediate guidance through a mechanism involving derepression of cytoplasmic domain multimerization. Activation of the adenosine A2B receptor, proposed to contribute to netrin effects on axons, is not required for rat commissural axon outgrowth or Xenopus spinal axon attraction to netrin-1. Thus, Stein et al. (2001) concluded that DCC plays a central role in netrin signaling of axon growth and guidance independent of A2B receptor activation. Note that an expression of concern was published for the article by Stein et al. (2001). </p><p>Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: they become repelled by the repellent Slit (603746) and simultaneously lose responsiveness to the attractant netrin. These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Stein and Tessier-Lavigne (2001) provided evidence that these 2 changes are causally linked: in the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Roundabout (Robo; 602430) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC. Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation. </p><p>In a 'whole-optic pathway' preparation in Xenopus devised to assess the behavior of retinal growth cones at 4 defined points along the optic pathway, Shewan et al. (2002) found a gradual change in axonal response to netrin-1, from attraction to repulsion at progressively distal points along the pathway. Axons aged in culture underwent similar changes which correlated with a decline in cAMP and netrin-1 receptor (ADORA2B; 600446) expression, suggesting that responsiveness is intrinsically and developmentally regulated, and also suggesting a possible molecular basis for the altered responsiveness. </p><p>Forcet et al. (2002) showed that in embryonic kidney cells expressing full-length, but not cytoplasmic domain-truncated, DCC (120470), NTN1 causes increased transient phosphorylation and activity of ERK1 (601795) and ERK2 (176948), but not of JNK1 (601158), JNK2 (602896), or p38 (MAPK14; 600289). This phosphorylation was mediated by MEK1 (MAP2K1; 176872) and/or MEK2 (MAP2K2; 601263). NTN1 also activated the transcription factor ELK1 (311040) and serum response element-regulated gene expression. Immunoprecipitation analysis showed interaction of full-length DCC with MEK1/2 in the presence or absence of NTN1. Forcet et al. (2002) showed that activation of Dcc by Ntn1 in rat embryonic day-13 dorsal spinal cord stimulates and is required for the outgrowth of commissural axons and Erk1/2 activation. Immunohistochemical analysis demonstrated expression of activated Erk1/2 in embryonic commissural axons, and this expression was diminished in Dcc or Ntn1 knockout animals. Forcet et al. (2002) concluded that the MAPK pathway is involved in responses to NTN1 and proposed that ERK activation affects axonal growth by phosphorylation of microtubule-associated proteins and neurofilaments. </p><p>Ming et al. (2002) found that axonal growth cones of cultured frog spinal neurons exhibit adaptation during chemotactic migration, undergoing consecutive phases of desensitization and resensitization in the presence of increasing basal concentrations of the guidance factors Ntn1 or Bdnf1 (113505). Ntn1- or Bdnf1-specific desensitization was accompanied by a reduction of calcium signaling, whereas resensitization required activation of Mapk and local protein synthesis. Ming et al. (2002) suggested that the protracted nature of this process allows adaptive changes in the sensitivity of the growth cone and that the adaptive behavior exemplifies the image of the growth cone as a chemotaking amoeba, as proposed in the 19th century by Ramon y Cajal. </p><p>Nishiyama et al. (2003) reported that the ratio of cyclic AMP to cyclic GMP activities sets the polarity of netrin-1-induced axon guidance: high ratios favor attraction, whereas low ratios favor repulsion. Whole-cell recordings of calcium currents in Xenopus spinal neuron growth cones indicated that cyclic nucleotide signaling directly modulates the activity of L-type calcium channels in axonal growth cones. Furthermore, cyclic GMP signaling activated by an arachidonate 12-lipoxygenase metabolite suppressed L-type calcium channel activity triggered by netrin-1, and was required for growth cone repulsion mediated by the DCC-UNC5 (see 603610) receptor complex. By linking cyclic AMP and cyclic GMP signaling and modulation of calcium channel activity in growth cones, these findings delineated an early membrane-associated event responsible for signal transduction during bidirectional axon guidance. </p><p>Mehlen et al. (1998) showed that DCC induces apoptosis conditionally: by functioning as a dependence receptor, DCC induces apoptosis unless it is engaged by its ligand netrin-1. Mazelin et al. (2004) demonstrated that inhibition of cell death by enforced expression of netrin-1 in mouse gastrointestinal tract led to the spontaneous formation of hyperplastic and neoplastic lesions. Moreover, in the adenomatous polyposis coli mutant background associated with adenoma formation, enforced expression of netrin-1 engendered aggressive adenocarcinomatous malignancies. Mazelin et al. (2004) concluded that netrin-1 can promote intestinal tumor development, probably by regulating cell survival. Thus, a netrin-1 receptor or receptors function as conditional tumor suppressors. </p><p>Blood vessels and nerves often follow with parallel trajectories, suggesting that distal targets use common cues that induce vascularization and innervation. Netrins are secreted by the floor plate and attract commissural axons toward the midline of the neural tube. Park et al. (2004) showed that netrin-1 is also a potent vascular mitogen. Netrin-1 stimulates proliferation, induces migration, and promotes adhesion of endothelial cells and vascular smooth muscle cells with a specific activity comparable to vascular endothelial growth factor (PEGF; 192240) and platelet-derived growth factor (PDGF; see 173430). The authors presented evidence indicating that the netrin receptor neogenin (NEO1; 601907) mediates netrin signaling in vascular smooth muscle cells, but suggested that an unidentified receptor mediates the proangiogenic effects of netrin-1 on endothelial cells. Netrin-1 also stimulates angiogenesis in vivo and augments the response to vascular endothelial growth factor. Park et al. (2004) concluded that netrin-1 is a secreted neural guidance cue with the unique ability to attract both blood vessels and axons and that other cues may also function as vascular endothelial growth factors. </p><p>Netrin proteins play a role in the developing nervous system by promoting both axonal outgrowth and axonal guidance in pathfinding. Liu et al. (2004), Li et al. (2004), and Ren et al. (2004) simultaneously reported a complex network of intracellular signaling downstream from netrin-1 involving DCC (120470), focal adhesion kinase (FAK; 600758), and FYN (137025), a member of the SRC family kinases (see 190090). In neurons cultured from rat cerebral cortex, Liu et al. (2004) found that netrin-1 induced tyrosine phosphorylation of FAK and FYN, and coimmunoprecipitation studies showed direct interaction of FAK and FYN with DCC. Inhibition of FYN inhibited FAK phosphorylation, and FYN mutants inhibited the attractive turning responses to netrin. Neurons lacking the FAK gene showed reduced axonal outgrowth and attractive turning responses to netrin. In cultured neurons from chick and mouse, Li et al. (2004) found that netrin increased tyrosine phosphorylation of DCC and FAK. Coimmunoprecipitation studies showed that DCC interacted directly with FAK and SRC to form a complex and that FAK and SRC cooperated to stimulate DCC phosphorylation by SRC. Li et al. (2004) suggested that phosphorylated DCC acts as a kinase-coupled receptor and that FAK and SRC act downstream of DCC in netrin signaling. Ren et al. (2004) found that inhibition of FAK phosphorylation inhibited netrin-1-induced axonal outgrowth and guidance. The authors suggested that FAK may also function as a scaffolding protein and play a role in cytoskeletal reorganization that is necessary for neurite outgrowth and turning. </p><p>Lu et al. (2004) showed that the repulsive netrin receptor UNC5B (607870) is expressed by endothelial tip cells of the vascular system. Disruption of the Unc5b gene in mice or of Unc5b or netrin-1A in zebrafish led to aberrant extension of endothelial tip cell filopodia, excessive vessel branching, and abnormal navigation. Netrin-1 caused endothelial filopodial retraction, but only when Unc5b was present. Thus, Lu et al. (2004) concluded that UNC5B functions as a repulsive netrin receptor in endothelial cells controlling morphogenesis of the vascular system. An Editorial Expression of Concern was published for the article by Lu et al. (2004) because image integrity issues had been raised about some of the images. The editors found that some panels of Supplementary Figure 2E appeared to have been duplicated, but noted that the authors provided contemporaneous replicates that confirmed the validity of the data presented in the figure. </p><p>Larrivee et al. (2007) found that Unc5b was downregulated in quiescent adult mouse vasculature, but it was reexpressed during sprouting angiogenesis in 3-dimensional gels and in tumor implants. Stimulation of Unc5b-expressing neovessels with netrin-1 inhibited sprouting angiogenesis, and genetic loss of Unc5b reduced netrin-1-mediated inhibition of angiogenesis. Expression of Unc5b triggered endothelial cell repulsion in response to netrin-1 in vitro, whereas a truncated Unc5b lacking the intracellular signaling domain failed to induce repulsion. Larrivee et al. (2007) concluded that activation of UNC5B by netrin-1 inhibits sprouting angiogenesis. </p><p>Wang and Poo (2005) reported that TRP (transient receptor potential)-like channel activity exists in the growth cones of cultured Xenopus neurons and can be modulated by exposure to netrin-1 and brain-derived neurotrophic factor (BDNF; 113505), 2 chemoattractants for axon guidance. Whole-cell recording from growth cones showed that netrin-1 induced a membrane depolarization, part of which remained after all major voltage-dependent channels were blocked. Furthermore, the membrane depolarization was sensitive to blockers of TRP channels. Pharmacologic blockade of putative TRP currents or downregulation of Xenopus TRP1 (xTRPC1) expression with a specific morpholino oligonucleotide abolished the growth cone turning and calcium ion elevation induced by a netrin-1 gradient. Thus, Wang and Poo (2005) concluded that TRPC currents reflect early events in the growth cone's detection of some extracellular guidance signal, resulting in membrane depolarization and cytoplasmic calcium ion elevation that mediates the turning of growth cones. </p><p>Wilson et al. (2006) demonstrated that netrins stimulate proliferation, migration, and tube formation of human endothelial cells in vitro and that this stimulation is independent of known netrin receptors. Suppression of netrin-1a mRNA in zebrafish inhibited vascular sprouting, implying a proangiogenic role for netrins during vertebrate development. Wilson et al. (2006) also showed that netrins accelerate neovascularization in an in vivo model of ischemia and that they reverse neuropathy and vasculopathy in a diabetic murine model. Wilson et al. (2006) found that vectors expressing netrin-1 and netrin-4 (NTN4; 610401) are comparable in effectiveness to vectors expressing VEGF (192240) and promoting neovascularization and reperfusion. </p><p>Colon-Ramos et al. (2007) showed that connectivity between 2 interneurons in C. elegans, AIY and RIA, is orchestrated by a pair of glial cells that express UNC6 (netrin-1). In the postsynaptic neuron RIA, the netrin receptor UNC40 (DCC; 120470) plays a conventional guidance role, directing outgrowth of the RIA process ventrally toward the glia. The authors demonstrated that in the presynaptic neuron AIY, UNC40 plays an unexpected and theretofore uncharacterized role: it cell-autonomously promotes assembly of presynaptic terminals in the immediate vicinity of the glial cell endfeet. Colon-Ramos et al. (2007) concluded that netrin can be used both for guidance and local synaptogenesis and suggested that glial cells can function as guideposts during the assembly of neural circuits in vivo. </p><p>Using cultured rat and frog spinal neurons, Ly et al. (2008) showed that Dscam (602523) could mediate the turning response to netrin-1 both alone and in collaboration with the netrin receptor Dcc. </p><p>Using primary neurons derived from rat, mouse, and chicken embryos, Furne et al. (2008) showed that Ntn1, in addition to behaving as an attractive cue, functioned in cell survival by inhibiting the proapoptotic activity of Dcc. </p><p>By quantitative RT-PCR of 51 primary breast tumors, Fitamant et al. (2008) found significantly increased expression of netrin-1 in a high proportion of lymph node-positive tumors and tumors from metastatic patients. Netrin-1-expressing mammary metastatic tumor cell lines underwent apoptosis when netrin-1 expression was experimentally decreased or when decoy soluble netrin receptor ectodomains were added. Such treatments prevented lung metastasis of a mammary cancer cell line and a xenografted human breast tumor in mice. Fitamant et al. (2008) concluded that netrin-1 expression confers a selective advantage for tumor cell survival. </p><p>Moore et al. (2009) showed that traction on immobilized netrin-1 was sufficient to reorient axons. </p><p>Delloye-Bourgeois et al. (2009) showed that autocrine production of NTN1 conveyed a selective advantage in tumor growth and dissemination in aggressive forms of neuroblastoma (NB; see 256700) by blocking the proapoptotic activity of the UNC5H receptors. NTN1 upregulation appeared to be a marker for poor prognosis in infants with stage 4S and stage 4 NB. NTN1 disruption blocked NB metastasis in animals, and Delloye-Bourgeois et al. (2009) proposed disrupting NTN1 expression as an anticancer strategy. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Xu et al. (2014) determined the structures of a functional NTN1 region, alone and in complexes with NEO1 (601907) and DCC (120470). NTN1 has a rigid elongated structure containing 2 receptor-binding sites at opposite ends through which it brings together receptor molecules. The ligand/receptor complexes reveal 2 distinct architectures: a 2:2 heterotetramer and a continuous ligand/receptor assembly. The differences result from different lengths of the linker connecting receptor domains fibronectin type III domain 4 (FN4) and FN5, which differs among DCC and NEO1 splice variants, providing a basis for diverse signaling outcomes. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Meyerhardt et al. (1999) mapped the human NTN1 gene to chromosome 17p13-p12 by FISH. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>In members of 2 unrelated families and in an unrelated patient with mirror movements-4 (MRMV4; 618264), Meneret et al. (2017) identified heterozygous mutations in the NTN1 gene (601614.0001-601614.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the condition in the 2 families; the patient in the third family had sporadic occurrence and the mutation occurred de novo. All mutations occurred in the NTR domain and were predicted to affect protein structure and/or stability. In vitro functional expression studies in HeLa and HEK293 cells showed that unlike wildtype, the mutant proteins were almost exclusively found in the intracellular compartments and could not be detected in the supernatant. Since netrin-1 is a diffusible extracellular cue, the pathophysiology probably involved a loss of function. The patients were ascertained from a cohort of 47 index cases with congenital mirror movements in whom mutations in other MRMV-associated genes were excluded. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Serafini et al. (1996) used the method of Skarnes et al. (1995) in embryonic stem cells to selectively recover mutations in genes encoding proteins with signal sequences by virtue of creating fusions of N-terminal portions of these proteins with an exogenous transmembrane domain. In this way Serafini et al. (1996) isolated a mutated murine netrin-1 gene and transmitted it through the germline. Homozygotes were born but apparently did not suckle and died within a few days. Netrin-1-deficient mice exhibited defects in spinal commissural axon projections that were considered consistent with netrin-1 guiding these axons. Defects in several forebrain commissures were also observed, suggesting additional guidance roles for netrin-1. </p><p>Poon et al. (2008) demonstrated that the axon guidance cue unc6/netrin and its receptor unc5 (607869) act throughout development to exclude synaptic vesicle and active zone proteins from the dendrite of the C. elegans motor neuron DA9, which is proximal to a source of unc6/netrin. In unc6/netrin and unc5 loss-of-function mutants, presynaptic components mislocalized to the DA9 dendrite. In addition, ectopically expressed unc6/netrin, acting through unc5, was sufficient to exclude endogenous synapses from adjacent subcellular domains within the DA9 axon. Furthermore, this antisynaptogenic activity was interchangeable with that of lin44/Wnt despite being transduced through different receptors, suggesting that extracellular cues such as netrin and Wnts not only guide axon navigation but also regulate the polarized accumulation of presynaptic components through local exclusion. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>3 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 MIRROR MOVEMENTS 4</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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NTN1, CYS601ARG
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<br />
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SNP: rs1567750186,
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ClinVar: RCV000735954
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<span class="mim-text-font">
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<p>In 3 affected members of a French family (family 1) with mirror movements-4 (MRMV4; 618264), Meneret et al. (2017) identified a heterozygous c.1801T-C transition (c.1801T-C, NM_004822) in exon 3 of the NTN1 gene, resulting in a cys601-to-arg (C601R) substitution at a highly conserved residue in the netrin domain. The mutation, which was found by exome sequencing, was not found in the ExAC database. There were 2 asymptomatic mutation carriers, indicating incomplete penetrance. In vitro functional expression studies in HeLa and HEK293 cells showed that unlike wildtype, the mutant protein was almost exclusively found in the intracellular compartments and could not be detected in the supernatant. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MIRROR MOVEMENTS 4</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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NTN1, 3-BP DEL, NT1552
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SNP: rs1567749982,
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ClinVar: RCV000735955
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 affected members of a family (family 2) with mirror movements-4 (MRMV4; 618264), Meneret et al. (2017) identified a heterozygous 3-bp deletion (c.1552_1554del, NM_004822) in exon 3 of the NTN1 gene, resulting in the deletion of conserved residue ile518 (Ile518del) in the netrin domain. The mutation, which was found by exome sequencing, was not found in the ExAC database. In vitro functional expression studies in HeLa and HEK293 cells showed that unlike wildtype, the mutant protein was almost exclusively found in the intracellular compartments and could not be detected in the supernatant. This family was previously reported as family C in Franz et al. (2015). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 MIRROR MOVEMENTS 4</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NTN1, CYS601SER
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<br />
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SNP: rs1567750187,
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ClinVar: RCV000735956
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (family 3) with sporadic occurrence of mirror movements-4 (MRMV4; 618264), Meneret et al. (2017) identified a heterozygous c.1802G-C transversion (c.1802G-C, NM_004822) in exon 3 of the NTN1 gene, resulting in a cys601-to-ser (C601S) substitution at a highly conserved residue in the netrin domain. The mutation, which was found by exome sequencing, was not found in the ExAC database. In vitro functional expression studies in HeLa and HEK293 cells showed that unlike wildtype, the mutant protein was almost exclusively found in the intracellular compartments and could not be detected in the supernatant. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<li>
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Corset, V., Nguyen-Ba-Charvet, K. T., Forcet, C., Moyse, E., Chedotal, A., Mehlen, P.
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<strong>Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor.</strong>
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Nature 407: 747-750, 2000.
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[PubMed: 11048721]
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Fitamant, J., Guenebeaud, C., Coissieux, M.-M., Guix, C., Treilleux, I., Scoazec, J.-Y., Bachelot, T., Bernet, A., Mehlen, P.
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<strong>Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer.</strong>
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[PubMed: 18353983]
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[Full Text: https://doi.org/10.1073/pnas.0709810105]
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<p class="mim-text-font">
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Forcet, C., Stein, E., Pays, L., Corset, V., Llambi, F., Tessier-Lavigne, M., Mehlen, P.
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<strong>Netrin-1-mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation.</strong>
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Nature 417: 443-447, 2002.
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[PubMed: 11986622]
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Franz, E. A., Chiaroni-Clarke, R., Woodrow, S., Glendining, K. A., Jasoni, C. L., Robertson, S. P., Gardner, R. J. M., Markie, D.
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<strong>Congenital mirror movements: phenotypes associated with DCC and RAD51 mutations.</strong>
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[Full Text: https://doi.org/10.1016/j.jns.2015.03.006]
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Furne, C., Rama, N., Corset, V., Chedotal, A., Mehlen, P.
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<strong>Netrin-1 is a survival factor during commissural neuron navigation.</strong>
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Proc. Nat. Acad. Sci. 105: 14465-14470, 2008.
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[PubMed: 18796601]
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[Full Text: https://doi.org/10.1073/pnas.0803645105]
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Galko, M. J., Tessier-Lavigne, M.
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<strong>Function of an axonal chemoattractant modulated by metalloprotease activity.</strong>
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Science 289: 1365-1367, 2000.
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[PubMed: 10958786]
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[Full Text: https://doi.org/10.1126/science.289.5483.1365]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hopker, V. H., Shewan, D., Tessier-Lavigne, M., Poo, M., Holt, C.
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<strong>Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1.</strong>
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Nature 401: 69-73, 1999.
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[PubMed: 10485706]
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[Full Text: https://doi.org/10.1038/43441]
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</p>
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<p class="mim-text-font">
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Larrivee, B., Freitas, C., Trombe, M., Lv, X., DeLafarge, B., Yuan, L., Bouvree, K., Breant, C., Del Toro, R., Brechot, N., Germain, S., Bono, F., Dol, F., Claes, F., Fischer, C., Autiero, M., Thomas, J.-L., Carmeliet, P., Tessier-Lavigne, M., Eichmann, A.
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<strong>Activation of the UNC5B receptor by netrin-1 inhibits sprouting angiogenesis.</strong>
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Genes Dev. 21: 2433-2447, 2007.
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[PubMed: 17908930]
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[Full Text: https://doi.org/10.1101/gad.437807]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Li, W., Lee, J., Vikis, H. G., Lee, S.-H., Liu, G., Aurandt, J., Shen, T.-L., Fearon, E. R., Guan, J.-L., Han, M., Rao, Y., Hong, K., Guan, K.-L.
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<strong>Activation of FAK and Src are receptor-proximal events required for netrin signaling.</strong>
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Nature Neurosci. 7: 1213-1221, 2004.
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[PubMed: 15494734]
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[Full Text: https://doi.org/10.1038/nn1329]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Liu, G., Beggs, H., Jurgensen, C., Park, H.-T., Tang, H., Gorski, J., Jones, K. R., Reichardt, L. F., Wu, J., Rao, Y.
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<strong>Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction.</strong>
|
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Nature Neurosci. 7: 1222-1232, 2004.
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[PubMed: 15494732]
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[Full Text: https://doi.org/10.1038/nn1331]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lu, X., le Noble, F., Yuan, L., Jiang, Q., de Lafarge, B., Sugiyama, D., Breant, C., Claes, F., De Smet, F., Thomas, J.-L., Autiero, M., Carmeliet, P., Tessier-Lavigne, M., Eichmann, A.
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<strong>The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system.</strong>
|
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Nature 432: 179-186, 2004. Note: Editorial Expression of Concern. Nature 625: E12, 2024.
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[PubMed: 15510105]
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[Full Text: https://doi.org/10.1038/nature03080]
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</p>
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<li>
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<p class="mim-text-font">
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Ly, A., Nikolaev, A., Suresh, G., Zheng, Y., Tessier-Lavigne, M., Stein, E.
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<strong>DSCAM is a netrin receptor that collaborates with DCC in mediating turning responses to netrin-1.</strong>
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Cell 133: 1241-1254, 2008.
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[PubMed: 18585357]
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[Full Text: https://doi.org/10.1016/j.cell.2008.05.030]
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<li>
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<p class="mim-text-font">
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Mazelin, L., Bernet, A., Bonod-Bidaud, C., Pays, L., Arnaud, S., Gespach, C., Bredesen, D. E., Scoazec, J.-Y., Mehlen, P.
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<strong>Netrin-1 controls colorectal tumorigenesis by regulating apoptosis.</strong>
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Nature 431: 80-84, 2004.
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[PubMed: 15343335]
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[Full Text: https://doi.org/10.1038/nature02788]
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<p class="mim-text-font">
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Mehlen, P., Rabizadeh, S., Snipas, S. J., Assa-Munt, N., Salvesen, G. S., Bredesen, D. E.
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<strong>The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis.</strong>
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Nature 395: 801-804, 1998.
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[PubMed: 9796814]
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[Full Text: https://doi.org/10.1038/27441]
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<p class="mim-text-font">
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Meneret, A., Franz, E. A., Trouillard, O., Oliver, T. C., Zagar, Y., Robertson, S. P., Weiniarz, Q., Gardner, R. J. M., Gallea, C., Srour, M., Depienne, C., Jasoni, C. L., and 15 others.
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<strong>Mutations in the netrin-1 gene cause congenital mirror movements.</strong>
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J. Clin. Invest. 127: 3923-3936, 2017.
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[PubMed: 28945198]
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<li>
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<p class="mim-text-font">
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Meyerhardt, J. A., Caca, K., Eckstrand, B. C., Hu, G., Lengauer, C., Banavali, S., Look, A. T., Fearon, E. R.
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<strong>Netrin-1: interaction with deleted in colorectal cancer (DCC) and alterations in brain tumors and neuroblastomas.</strong>
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[PubMed: 9950216]
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<p class="mim-text-font">
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Ming, G., Wong, S. T., Henley, J., Yuan, X., Song, H., Spitzer, N. C., Poo, M.
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<strong>Adaptation in the chemotactic guidance of nerve growth cones.</strong>
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[PubMed: 11986620]
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<p class="mim-text-font">
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Moore, S. W., Biais, N., Sheetz, M. P.
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<strong>Traction on immobilized netrin-1 is sufficient to reorient axons.</strong>
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Science 325: 166 only, 2009.
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[PubMed: 19589994]
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[Full Text: https://doi.org/10.1126/science.1173851]
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<li>
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<p class="mim-text-font">
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Nishiyama, M., Hoshino, A., Tsai, L., Henley, J. R., Goshima, Y., Tessier-Lavigne, M., Poo, M., Hong, K.
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<strong>Cyclic AMP/GMP-dependent modulation of Ca(2+) channels sets the polarity of nerve growth-cone turning.</strong>
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</p>
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<li>
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<p class="mim-text-font">
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Park, K. W., Crouse, D., Lee, M., Karnik, S. K., Sorensen, L. K., Murphy, K. J., Kuo, C. J., Li, D. Y.
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<strong>The axonal attractant netrin-1 is an angiogenic factor.</strong>
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[PubMed: 15520390]
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</p>
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<p class="mim-text-font">
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Poon, V. Y., Klassen, M. P., Shen, K.
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<strong>UNC-6/netrin and its receptor UNC-5 locally exclude presynaptic components from dendrites.</strong>
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Nature 455: 669-673, 2008.
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[PubMed: 18776887]
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[Full Text: https://doi.org/10.1038/nature07291]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ren, X., Ming, G., Xie, Y., Hong, Y., Sun, D., Zhao, Z., Feng, Z., Wang, Q., Shim, S., Chen, Z., Song, H., Mei, L., Xiong, W.
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<strong>Focal adhesion kinase in netrin-1 signaling.</strong>
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|
Nature Neurosci. 7: 1204-1212, 2004.
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[PubMed: 15494733]
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[Full Text: https://doi.org/10.1038/nn1330]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Serafini, T., Colamarino, S. A., Leonardo, E. D., Wang, H., Beddington, R., Skarnes, W. C., Tessier-Lavigne, M.
|
|
<strong>Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system.</strong>
|
|
Cell 87: 1001-1014, 1996.
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|
[PubMed: 8978605]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)81795-x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Shewan, D., Dwivedy, A., Anderson, R., Holt, C. E.
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|
<strong>Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway.</strong>
|
|
Nature Neurosci. 5: 955-962, 2002.
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|
|
[PubMed: 12352982]
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|
[Full Text: https://doi.org/10.1038/nn919]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Skarnes, W. C., Moss, J. E., Hurtley, S. M., Beddington, R. S. P.
|
|
<strong>Capturing genes encoding membrane and secreted proteins important for mouse development.</strong>
|
|
Proc. Nat. Acad. Sci. 92: 6592-6596, 1995.
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|
|
[PubMed: 7604039]
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|
[Full Text: https://doi.org/10.1073/pnas.92.14.6592]
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</p>
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<li>
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<p class="mim-text-font">
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|
Stein, E., Tessier-Lavigne, M.
|
|
<strong>Hierarchical organization of guidance receptors: silencing of netrin attraction by Slit through a Robo/DCC receptor complex.</strong>
|
|
Science 291: 1928-1938, 2001. Note: Expression of Concern: Science 378: 1284 only, 2022.
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[PubMed: 11239147]
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[Full Text: https://doi.org/10.1126/science.1058445]
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<p class="mim-text-font">
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Stein, E., Zou, Y., Poo, M., Tessier-Lavigne, M.
|
|
<strong>Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation.</strong>
|
|
Science 291: 1976-1982, 2001. Note: Expression of Concern: Science 378: 1284 only, 2022.
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[PubMed: 11239160]
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Wilson, B. D., Li, M., Park, K. W., Suli, A., Sorensen, L. K., Larrieu-Lahargue, F., Urness, L. D., Suh, W., Asai, J., Kock, G. A. H., Thorne, T., Silver, M., Thomas, K. R., Chien, C.-B., Losordo, D. W., Li, D. Y.
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Xu, K., Wu, Z., Renier, N., Antipenko, A., Tzvetkova-Robev, D., Xu, Y., Minchenko, M., Nardi-Dei, V., Rajashankar, K. R., Himanen, J., Tessier-Lavigne, M., Nikolov, D. B.
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Cassandra L. Kniffin - updated : 01/02/2019<br>Ada Hamosh - updated : 7/7/2014<br>Paul J. Converse - updated : 11/12/2009<br>Patricia A. Hartz - updated : 8/31/2009<br>Ada Hamosh - updated : 8/14/2009<br>Ada Hamosh - updated : 11/5/2008<br>Patricia A. Hartz - updated : 9/10/2008<br>Patricia A. Hartz - updated : 8/13/2008<br>Patricia A. Hartz - updated : 11/2/2007<br>Ada Hamosh - updated : 10/26/2007<br>Ada Hamosh - updated : 6/27/2007<br>Anne M. Stumpf - updated : 9/8/2006<br>Ada Hamosh - updated : 9/6/2006<br>Ada Hamosh - updated : 9/19/2005<br>Cassandra L. Kniffin - updated : 2/8/2005<br>Victor A. McKusick - updated : 12/30/2004<br>Ada Hamosh - updated : 11/10/2004<br>Ada Hamosh - updated : 7/8/2003<br>Cassandra L. Kniffin - updated : 9/30/2002<br>Paul J. Converse - updated : 5/6/2002<br>Ada Hamosh - updated : 3/27/2001<br>Ada Hamosh - updated : 3/27/2001<br>Ada Hamosh - updated : 10/18/2000<br>Ada Hamosh - updated : 9/5/2000<br>Ada Hamosh - updated : 2/14/2000
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Victor A. McKusick : 1/8/1997
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