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Other entities represented in this entry:
HGNC Approved Gene Symbol: WNT3
Cytogenetic location: 17q21.31-q21.32 Genomic coordinates (GRCh38) : 17:46,762,506-46,818,692 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31-q21.32 | ?Tetra-amelia syndrome 1 | 273395 | Autosomal recessive | 3 |
Roelink et al. (1993) used mouse Wnt3 sequences as a probe to isolate a genomic clone of the human homolog, WNT3. Comparison of the deduced mouse and human WNT3 protein sequences showed 4 changes in 333 amino acids.
Using ribonuclease protection analysis, Huguet et al. (1994) investigated expression of WNT genes, including WNT3, in human cell lines, as well as in normal, benign, and malignant breast tissue. They detected WNT3 in breast cell lines and in breast tissue.
Rider et al. (1989) assigned the INT4 gene to 17q21-q22 using a DNA probe in the study of a panel of chromosome-mediated gene transfectants and conventional hybrids, in particular those with well-defined breaks on human chromosome 17. In situ hybridization was performed for more precise localization. The mouse MMTV integration site int4 was mapped to mouse chromosome 11 in a region homologous to the region of human chromosome 17 carrying the INT4 locus.
Roelink et al. (1993) localized the WNT3 gene to chromosome 17q21 by isotopic in situ hybridization.
Several studies had implicated Wnt signaling in primary axis formation during vertebrate embryogenesis, yet no Wnt protein had been shown to be essential for this process. In the mouse, primitive streak formation is the first overt morphologic sign of the anterior-posterior axis in mesoderm. Liu et al. (1999) generated Wnt3 -/- mice by targeted disruption of the mouse Wnt3 gene. Wnt3 -/- mice developed a normal egg cylinder but did not form a primitive streak, mesoderm, or node. The epiblast continued to proliferate in an undifferentiated state that lacked anterior-posterior neural patterning, but anterior visceral endoderm markers were expressed and correctly positioned. Liu et al. (1999) concluded that regional patterning of the visceral endoderm is independent of primitive streak formation, but the subsequent establishment of anterior-posterior neural pattern in the ectoderm is dependent on derivatives of the primitive streak. Their studies provided genetic proof for the requirement of Wnt3 in primary axis formation in the mouse.
Krylova et al. (2002) investigated the role of Wnt proteins in the formation of the sensorimotor connections in the mouse spinal cord. Using in situ hybridization, they detected Wnt3 gene expression in motoneurons of the lateral motor column at a time when sensory axons make contact with them. In neuronal cultures, Wnt3 increased branching and growth cone size while inhibiting axonal extension in axons responsive to neurotrophin-3 (Ntf3; 162660), but not in axons responsive to nerve growth factor (NGF). In explant cultures, the ventral spinal cord secreted factors with Wnt3-like axonal remodeling activity that was blocked by Sfrp1 (604156), a Wnt antagonist. Krylova et al. (2002) concluded that WNT3 acts as a retrograde branching and stop signal for muscle afferents during the formation of sensorimotor circuits in the spinal cord.
Lie et al. (2005) demonstrated that adult hippocampal stem/progenitor cells (AHPs) express receptors and signaling components for Wnt proteins, which are key regulators of neural stem behavior in embryonic development. Lie et al. (2005) also showed that the Wnt/beta-catenin (116806) pathway is active and that Wnt3 is expressed in the hippocampal neurogenic niche. Overexpression of Wnt3 was sufficient to increase neurogenesis from AHPs in vitro and in vivo. By contrast, blockade of Wnt signaling reduced neurogenesis from AHPs in vitro and abolished neurogenesis almost completely in vivo. Lie et al. (2005) concluded that their data showed that Wnt signaling is a principal regulator of adult hippocampal neurogenesis and provided evidence that Wnt proteins have a role in adult hippocampal function.
Schmitt et al. (2006) found that Wnt3 is expressed in a medial-lateral decreasing gradient in chick optic tectum and mouse superior colliculus. Retinal ganglion cell axons from different dorsal-ventral positions showed graded and biphasic response to Wnt3 in a concentration-dependent manner. Wnt3 repulsion is mediated by Ryk (600524), expressed in a ventral-to-dorsal decreasing gradient, whereas attraction of dorsal axons at lower Wnt3 concentrations is mediated by Frizzled(s) (see 603408). Overexpression of Wnt3 in the lateral tectum repelled the termination zones of dorsal retinal ganglion cell axons in vivo. Expression of a dominant-negative Ryk in dorsal retinal ganglion cell axons caused a medial shift of the termination zones, promoting medially directed interstitial branches and eliminating laterally directed branches. Therefore, Schmitt et al. (2006) concluded that a classic morphogen, Wnt3, acting as an axon guidance molecule, plays a role in retinotectal mapping along the medial-lateral axis, counterbalancing the medial-directed EphrinB1-EphB (see 300035) activity.
Farin et al. (2016) generated an epitope-tagged functional Wnt3 knockin allele. Wnt3 covers basolateral membranes of neighboring stem cells. In intestinal organoids Wnt3 transfer involves direct contact between Paneth cells and stem cells. Plasma membrane localization requires surface expression of Frizzled receptors, which in turn is regulated by the transmembrane E3 ligases RNF43 (612482) and ZNRF3 (612062) and their antagonists LGR4 (606666), LGR5 (606667), and R-spondin (609595). By manipulating Wnt3 secretion and by arresting stem cell proliferation, Farin et al. (2016) demonstrated that Wnt3 travels away from its source in a cell-bound manner through cell division, and not through diffusion. The authors concluded that stem cell membranes constitute a reservoir for Wnt proteins, while frizzled receptor turnover and plasma membrane dilution through cell division shape the epithelial Wnt3 gradient.
In 4 affected fetuses of a consanguineous Turkish family with autosomal recessive tetraamelia syndrome (TETAMS1; 273395), Niemann et al. (2004) identified a homozygous nonsense mutation in the WNT3 gene (165330.0001). Based on the phenotypic findings in the affected patients, Niemann et al. (2004) concluded that WNT3 is required at the early stages of limb formation, as well as for craniofacial and urogenital development.
For the group of related genes of which the first to be discovered was INT1 (164820), Nusse et al. (1991) suggested the designation Wnt (pronounced 'wint'), a mnemonic for the 'wingless' homolog. The product INT1 (renamed WNT1) encodes a novel secretory glycoprotein similar to the product of the Drosophila melanogaster 'wingless' gene. The INT4 locus was renamed WNT3.
In 4 affected fetuses of a consanguineous Turkish family with autosomal recessive tetraamelia syndrome (TETAMS1; 273395), Niemann et al. (2004) identified a homozygous c.366C-T transition in the WNT3 gene, resulting in a gln83-to-ter (Q83X) mutation. The mutation was predicted to result in a truncated protein of only 82 amino acids. Hence, loss of function of both copies of WNT3 is the most likely pathogenic mechanism in these patients.
Farin, H. F., Jordens, I., Mosa, M. H., Basak, O., Korving, J., Tauriello, D. V. F., de Punder, K., Angers, S., Peters, P. J., Maurice, M. M., Clevers, H. Visualization of a short-range Wnt gradient in the intestinal stem-cell niche. Nature 530: 340-343, 2016. [PubMed: 26863187] [Full Text: https://doi.org/10.1038/nature16937]
Huguet, E. L., McMahon, J. A., McMahon, A. P., Bicknell, R., Harris, A. L. Differential expression of human Wnt genes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue. Cancer Res. 54: 2615-2621, 1994. [PubMed: 8168088]
Krylova, O., Herreros, J., Cleverley, K. E., Ehler, E., Henriquez, J. P., Hughes, S. M., Salinas, P. C. WNT-3, expressed by motoneurons, regulates terminal arborization of neurotrophin-3-responsive spinal sensory neurons. Neuron 35: 1043-1056, 2002. [PubMed: 12354395] [Full Text: https://doi.org/10.1016/s0896-6273(02)00860-7]
Lie, D.-C., Colamarino, S. A., Song, H.-J., Desire, L., Mira, H., Consiglio, A., Lein, E. S., Jessberger, S., Lansford, H., Dearie, A. R., Gage, F. H. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437: 1370-1375, 2005. [PubMed: 16251967] [Full Text: https://doi.org/10.1038/nature04108]
Liu, P., Wakamiya, M., Shea, M. J., Albrecht, U., Behringer, R. R., Bradley, A. Requirement for Wnt3 in vertebrate axis formation. Nature Genet. 22: 361-365, 1999. [PubMed: 10431240] [Full Text: https://doi.org/10.1038/11932]
Niemann, S., Zhao, C., Pascu, F., Stahl, U., Aulepp, U., Niswander, L., Weber, J. L., Muller, U. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am. J. Hum. Genet. 74: 558-563, 2004. [PubMed: 14872406] [Full Text: https://doi.org/10.1086/382196]
Nusse, R., Brown, A., Papkoff, J., Scambler, P., Shackleford, G., McMahon, A., Moon, R., Varmus, H. A new nomenclature for int-1 and related genes: the Wnt gene family. Cell 64: 231-232, 1991. [PubMed: 1846319] [Full Text: https://doi.org/10.1016/0092-8674(91)90633-a]
Rider, S. H., Gorman, P. A., Shipley, J., Roeling, H., Nusse, R., Xu, W., Sheer, D., Solomon, E. Localisation of the human int-4 (INT4) gene. (Abstract) Cytogenet. Cell Genet. 51: 1066 only, 1989.
Roelink, H., Wang, J., Black, D. M., Solomon, E., Nusse, R. Molecular cloning and chromosomal localization to 17q21 of the human WNT3 gene. Genomics 17: 790-792, 1993. [PubMed: 8244403] [Full Text: https://doi.org/10.1006/geno.1993.1412]
Schmitt, A. M., Shi, J., Wolf, A. M., Lu, C.-C., King, L. A., Zou, Y. Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping. Nature 439: 31-37, 2006. [PubMed: 16280981] [Full Text: https://doi.org/10.1038/nature04334]