Entry - *190198 - NOTCH RECEPTOR 1; NOTCH1

Notch proteins are single-pass transmembrane receptors that regulate cell fate decisions during development. The Notch family includes 4 receptors, NOTCH1, NOTCH2 (600275), NOTCH3 (600276), and NOTCH4 (164951), whose ligands include JAG1 (601920), JAG2 (602570), DLL1 (606582), DLL3 (602768), and DLL4 (605185). All of the receptors have an extracellular domain containing multiple epidermal growth factor (EGF; 131530)-like repeats and an intracellular region containing the RAM domain, ankyrin repeats, and a C-terminal PEST domain (Das et al., 2004).

▼ Cloning and Expression

In a translocation t(7;9)(q34;q34.3) found in a case of acute T-cell lymphoblastic leukemia, Ellisen et al. (1991) found that the locus on chromosome 9 contains a gene, NOTCH1, highly homologous to the Drosophila gene Notch. Transcripts of the human NOTCH1 gene, which Ellisen et al. (1991) called TAN1, and its murine counterpart were demonstrated in many normal human fetal and adult mouse tissues, but were most abundant in lymphoid tissues.

Milner et al. (1994) found that at least 1 Notch homolog was expressed in human bone marrow CD34 (142230)-positive cells, a population enriched for hematopoietic precursors. On the basis of these findings, they suggested that members of the Notch family, including TAN1, may be involved in mediating cell-fate decisions during hematopoiesis.

In addition to the EGF-like repeats in the extracellular region of Notch, known motifs in the intracellular region of Notch include a nuclear localization signal (NLS) and a RAM motif, 6 ankyrin/CDC10 repeats, a second NLS, PEST sequences, and a glutamine-rich domain. By luciferase and Western blot analysis, Wang et al. (2001) determined that a highly conserved 109-amino acid region (residues 1773-1881) N-terminal of the 6 ankyrin repeats of intracellular NOTCH1 inhibits NFKB (164011) DNA binding and gene expression. They termed this protein-protein interaction domain, which includes an NLS, the NFKB-binding domain.

▼ Biochemical Features

Crystal Structure

Luca et al. (2015) determined the crystal structure of the interacting regions of the NOTCH1-DLL4 complex at 2.3-angstrom resolution. The complex reveals a 2-site, antiparallel binding orientation assisted by NOTCH1 O-linked glycosylation. NOTCH1 EGF-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag2 (DSL) domain and module at the N terminus of Notch ligand (MNNL) domains, respectively. Threonine and serine residues on NOTCH1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific and essential contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in NOTCH1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.

Luca et al. (2017) determined the 2.5-angstrom-resolution crystal structure of the extracellular interacting region of Notch1 complexed with an engineered, high-affinity variant of Jag1. The structure revealed a binding interface that extends approximately 120 angstroms along 5 consecutive domains of each protein. O-Linked fucose modifications on Notch1 EGF domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch1 domains are favored in binding to Jag1 than those that bind to the Dll4 ligand. Jag1 undergoes conformational changes upon Notch binding, exhibiting catch bond behavior that prolongs interactions in the range of forces required for Notch activation. This mechanism enables cellular forces to regulate binding, discriminate among Notch ligands, and potentiate Notch signaling.

Cryoelectron Microscopy

Yang et al. (2019) reported the cryoelectron microscopy structure of human gamma-secretase (see PS1, 104311) in complex with a Notch fragment at a resolution of 2.7 angstroms. The transmembrane helix of Notch is surrounded by 3 transmembrane domains of PS1, and the carboxyl-terminal beta-strand of the Notch fragment forms a beta-sheet with 2 substrate-induced beta-strands of PS1 on the intracellular side. Formation of the hybrid beta-sheet is essential for substrate cleavage, which occurs at the carboxyl-terminal end of the Notch transmembrane helix. PS1 undergoes pronounced conformational rearrangement upon substrate binding. Yang et al. (2019) concluded that these features reveal the structural basis of Notch recognition and have implications for the recruitment of the amyloid precursor protein by gamma-secretase.

▼ Mapping

By analysis of somatic cell hybrids and FISH, Larsson et al. (1994) mapped the NOTCH1 gene to chromosome 9q34. They mapped the NOTCH2 and NOTCH3 genes to chromosomes 1p13-p11 and 19p13.2-p13.1, respectively.

Del Amo et al. (1993) and Pilz et al. (1994) demonstrated that the mouse Notch1 gene maps to chromosome 2.

▼ Gene Function

Notch Ligand Selectivity

To identify the specific domains in the Notch receptor responsible for ligand selectivity, Yamamoto et al. (2012) performed genetic screens in Drosophila and isolated a mutation, Notch(Jigsaw), that affects Serrate- but not Delta-dependent signaling. Notch(Jigsaw) carries a missense mutation in epidermal growth factor repeat-8 (Egfr-8) and is defective in Serrate binding. A homologous point mutation in mammalian Notch2 (600275) results in defects in signaling of a mammalian Serrate homolog, Jagged1 (601920). Yamamoto et al. (2012) concluded that an evolutionarily conserved valine in Egfr-8 is essential for ligand selectivity and provides a molecular handle to study numerous Notch-dependent signaling events.

Processing of Notch

There is proteolytic processing in maturation and activation of NOTCH1 (Chan and Jan, 1998). Maturation of the NOTCH1 protein is mediated by a furin (136950)-like convertase within the secretory pathway; cleavage occurs at an extracellular site, called site 1 (S1), after the recognition sequence RQRR (Logeat et al., 1998). The resultant polypeptides associate as an intramolecular heterodimer thought to be the only form of the NOTCH1 receptor found on the cell surface (Logeat et al., 1998). Activation of NOTCH1 involves cleavage between gly1743 and val1744 (termed site 3, or S3) (Schroeter et al., 1998). S3 cleavage serves to release the NOTCH1 intracellular domain (NICD) from the membrane. NICD then translocates to the nucleus, where it functions as a transcriptional activator in concert with CSL family members (RBPSUH (147183), 'suppressor of hairless,' and LAG1) (Jarriault et al., 1995). S3 processing occurs only in response to ligand binding. Mumm et al. (2000) demonstrated that ligand binding facilitates cleavage at another site, which they named S2, within the extracellular juxtamembrane region. This serves to release ectodomain repression of NICD production. S2 cleavage occurs between ala1710 and val1711, approximately 12 amino acids outside the transmembrane domain. Cleavage at S2 generates a transient intermediate peptide termed NEXT (Notch extracellular truncation). NEXT accumulates when NICD production is blocked by point mutations or gamma-secretase inhibitors, or by loss of presenilin-1 (PSEN1; 104311), and inhibition of NEXT eliminates NICD production. These data demonstrated that S2 cleavage is a ligand-regulated step in the proteolytic cascade leading to NOTCH1 activation.

Brou et al. (2000) purified the gamma-secretase-like activity that accounts for the S2 cleavage in vitro and showed that it is due to tumor necrosis factor-converting enzyme, or TACE (ADAM17; 603639), a member of the ADAM family of metalloproteases. Furthermore, experiments on TACE -/- bone marrow-derived monocytic precursor cells suggested that TACE plays a prominent role in the activation of the Notch pathway.

Role of Presenilins in Notch Processing

The connection between Notch and the presenilins (PSEN1, 104311; PSEN2, 600759) was indicated by the work of De Strooper et al. (1999), Struhl and Greenwald (1999), and Ye et al. (1999). Struhl and Greenwald (1999) and Ye et al. (1999) showed that loss-of-function mutations in the Drosophila presenilin gene exhibited a lethal Notch-like phenotype. De Strooper et al. (1999) investigated the effect of presenilin on Notch processing by introducing a constitutively active form of murine Notch1 into fibroblasts derived from presenilin-1 knockout mice. This construct had previously been used to identify a proteolytic cleavage site located in or near the transmembrane region of Notch. All 3 groups concluded that presenilin is required for release of the intracellular domain of Notch from the plasma membrane. The significance of this work was discussed by Hardy and Israel (1999). By analyzing a Psen1 conditional knockout mouse, Yu et al. (2001) concluded that inactivation of Psen1 function in the adult cerebral cortex does not affect expression of Notch downstream target genes.

A major therapeutic target in the search for a cure for Alzheimer disease (104300) is gamma-secretase. This activity resides in a multiprotein enzyme complex responsible for the generation of A-beta-42 peptides, precipitates of which are thought to cause Alzheimer disease. Presenilins are thought to contain the active site for gamma-secretase. Gamma-secretase is also a critical component of the Notch signal transduction pathway; Notch signals regulate development and differentiation of adult self-renewing cells. This fact led to concern that therapeutic inhibition of gamma-secretase may interfere with Notch-related processes in adults, most alarmingly in hematopoiesis. Hadland et al. (2001) showed that application of gamma-secretase inhibitors to fetal thymus organ cultures interfered with T-cell development in a manner consistent with loss or reduction of Notch1 function. Progression from an immature CD4-/CD8- state to an intermediate CD4+/CD8+ double-positive state was repressed. Furthermore, treatment beginning later at the double-positive stage specifically inhibited CD8+ single-positive maturation but did not affect CD4+ single-positive cells. These results demonstrated that pharmacologic gamma-secretase inhibition recapitulates Notch1 loss in a vertebrate tissue and presented a system in which rapid evaluation of gamma-secretase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed.

Modulation of Notch Signaling by Fringe Proteins

Notch receptors function in highly conserved intercellular signaling pathways that direct cell-fate decisions, proliferation, and apoptosis in metazoans. Fringe proteins, such as 'lunatic fringe' (LFNG; 602576), can positively and negatively modulate the ability of Notch ligands to activate the Notch receptor. Moloney et al. (2000) established the biochemical mechanism of Fringe action. Drosophila and mammalian Fringe proteins possess a fucose-specific beta-1,3 N-acetylglucosaminyltransferase activity that initiates elongation of O-linked fucose residues attached to epidermal growth factor (EGF; 131530)-like sequence repeats of Notch. Moloney et al. (2000) obtained biologic evidence that Fringe-dependent elongation of O-linked fucose on Notch modulates Notch signaling by using coculture assays in mammalian cells and by expression of an enzymatically inactive Fringe mutant in Drosophila. The authors stated that the posttranslational modification of Notch by Fringe represents a striking example of modulation of a signaling event by differential receptor glycosylation and identifies a mechanism they considered likely to be relevant to other signaling pathways.

Studying Drosophila, Bruckner et al. (2000) showed that Fringe acts in the Golgi as a glycosyltransferase enzyme that modifies the EGF modules of Notch and alters the ability of Notch to bind its ligand Delta (602768). The authors demonstrated that Fringe catalyzes the addition of N-acetylglucosamine to fucose, which is consistent with a role in the elongation of O-linked fucose O-glycosylation that is associated with EGF repeats. They suggested that cell type-specific modification of glycosylation may provide a general mechanism to regulate ligand-receptor interactions in vivo.

Visan et al. (2006) found that developmental stage-specific expression of Lfng was required for coordinating access of mouse T-cell progenitors to intrathymic niches supporting Notch1-dependent phases of T-cell development. Progenitors lacking Lfng generated few thymocytes in competitive assays, whereas overexpression of Lfng resulted in 'supercompetitive' thymocytes that showed enhanced binding to delta-like ligands (e.g., DLL1) and blocked T lymphopoiesis by normal progenitors. Visan et al. (2006) proposed that LFNG and NOTCH1 control of progenitor competition for cortical niches that suppress the B-cell potential of progenitors is important in regulation of thymus size.

Modulation of Notch Signaling by POFUT1

Notch and its ligands are modified by POFUT1 (607491), which attaches fucose to a serine or threonine within EGF domains. Using RNA interference to decrease Pofut1 expression in Drosophila, Okajima and Irvine (2002) demonstrated that O-linked fucose is positively required for Notch signaling, including both fringe-dependent and fringe-independent processes. The requirement for Pofut1 was found to be cell autonomous, in the signal-receiving cell, and upstream of Notch activation. The transcription of Pofut1 was developmentally regulated, and overexpression of Pofut1 inhibited Notch signaling. The authors concluded that POFUT1 is a core component of the Notch pathway that is required for the activation of Notch by its ligands and whose regulation may contribute to the pattern of Notch activation during development.

Modulation of Notch Signaling by PIN1

Rustighi et al. (2009) showed that PIN1 (601052) enhanced NOTCH1 signaling in human cancer cell lines through its prolyl-isomerase activity. PIN1 interacted directly with phosphorylated NOTCH1 and enhanced NOTCH1 cleavage by gamma-secretase. Accordingly, PIN1 contributed to NOTCH1 transforming properties both in vitro and in vivo. NOTCH1 in turn upregulated PIN1, thus establishing a positive feedback loop that amplified NOTCH1 signaling.

Modulation of Notch Signaling by USP10

Lim et al. (2019) found that human USP10 (609818) interacted with NICD to slow ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Inactivation of USP10 reduced NICD abundance and stability and diminished Notch-induced target gene expression in human endothelial cells. In mice, loss of endothelial Usp10 increased vessel sprouting and partially restored patterning defects caused by ectopic expression of NICD. The authors concluded that USP10 functions as an NICD deubiquitinase that modulates endothelial Notch responses during angiogenic sprouting.

Notch Signaling Pathway

Artavanis-Tsakonas et al. (1995) reviewed the Notch signaling pathway.

Axelrod et al. (1996) reported that the Drosophila Dishevelled gene (601225), which encodes a component of the Wingless (164820) signaling pathway, interacts antagonistically with Notch and one of its ligands, Delta. A direct physical interaction between Dishevelled and the Notch C terminus suggested to the authors that Dishevelled blocks Notch signaling directly and provides a molecular mechanism for the inhibitory crosstalk observed between the Notch and Wingless signaling pathways.

Rangarajan et al. (2001) found that Notch1 activation induced p21 (CDKN1A; 116899) in differentiating mouse keratinocytes, and the induction was associated with the targeting of Rbpjk (RBPSUH; 147183) to the p21 promoter. Mammucari et al. (2005) showed that Notch1 also activated p21 through a calcineurin (see 114105)-dependent mechanism acting on the p21 TATA box-proximal region. Notch signaling through the calcineurin/NFAT (see 600490) pathway also involved calcipressin (see 602917) and Hes1.

Weijzen et al. (2002) demonstrated that oncogenic Ras (190020) activates Notch signaling and that wildtype Notch1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wildtype Notch1, and upregulates Notch1 ligand Delta1 (606582) and also presenilin-1 (104311), a protein involved in Notch processing, through a p38 (600289)-mediated pathway. Weijzen et al. (2002) concluded that their observations placed Notch signaling among key downstream effectors of oncogenic Ras.

Balint et al. (2005) demonstrated that the NOTCH1 pathway was activated in melanoma (see 155600) specimens compared to nevus specimens. Blocking NOTCH signaling suppressed primary melanoma cell growth, whereas constitutive activation of the NOTCH1 pathway enhanced primary melanoma cell growth both in vitro and in vivo, but NOTCH1 had little effect on metastatic melanoma cells. Activation of NOTCH1 signaling enabled primary melanoma cells to gain metastatic capability. The oncogenic effect of NOTCH1 on primary melanoma cells was mediated by beta-catenin, which was upregulated following NOTCH1 activation; inhibiting beta-catenin expression reversed NOTCH1-enhanced tumor growth and metastasis. Balint et al. (2005) suggested that there is a beta-catenin-dependent, stage-specific role for NOTCH1 signaling in promoting the progression of primary melanoma.

Using microarray studies of the mouse presomitic mesoderm transcriptome, Dequeant et al. (2006) demonstrated that the oscillator associated with this process, the segmentation clock, drives the periodic expression of a large network of cyclic genes involved in cell signaling. Mutually exclusive activation of the Notch-fibroblast growth factor (FGF) and Wnt (see 164820) pathways during each cycle suggested that coordinated regulation of these 3 pathways underlies the clock oscillator. Dequeant et al. (2006) collected presomitic mesoderm samples from 40 mouse embryos ranging from 19 to 23 somites and used their Lfng (602576) expression patterns as a proxy to select 17 samples covering an entire oscillation cycle. Six of the 8 known mouse cyclic genes, Hes1 (139605), Hes5 (607348), Hey1 (602953), Lfng, Axin2 (604025), and Nkd1 (607851), were identified with periods of 94, 102, 112, 81, 102, and 112 minutes, respectively. Two clusters were identified. One cluster contains the known cyclic genes of the Notch pathway: Hes1, Hes5, and Hey1, as well as Id1 (600349). This cluster also contains Nrarp (619987), a direct target of Notch signaling. In the same cluster as the Notch pathway were members of the FGF-MAPK pathway, including Spry2 (602466) and Dusp6 (602748). The second cluster of periodic genes contained genes cycling in opposite phase to the Notch-FGF cluster; in this cluster were a majority of the cyclic genes associated with Wnt signaling, including Dkk1 (605189), cMyc (190080), Axin2, Sp5 (609391), and Tnfrsf19 (606122).

By examining gene expression profiles, Palomero et al. (2006) found that NOTCH and MYC (190080) regulate 2 interconnected transcriptional programs containing common target genes that regulate cell growth in primary human T-cell lymphoblastic leukemias.

In studies involving bone marrow progenitor cells and T-cell acute lymphoblastic leukemia (T-ALL) cell lines, Vilimas et al. (2007) found that constitutively active NOTCH1 activated the NFKB pathway transcriptionally and via the IKK complex (see 600664), thereby causing increased expression of NFKB target genes. The NFKB pathway was highly active in establishing human T-ALL, and inhibition of the pathway efficiently restricted tumor growth both in vitro and in vivo. Vilimas et al. (2007) concluded that NFKB is one of the major mediators of NOTCH1-induced transformation.

Lefort et al. (2007) found that NOTCH1 protein and mRNA were reduced in a panel of skin and oral squamous cell carcinoma (SCC) cell lines and in a panel of skin SCCs relative to normal epidermis controls. They found that inhibition of Notch signaling in human primary keratinocytes suppressed keratinocyte commitment to differentiation, expanded a cell population with stem cell potential, and promoted aggressive SCC formation. Expression of NOTCH1 in human keratinocytes was under the control of P53 (TP53; 191170), and NOTCH1 suppressed tumor formation through negative regulation of ROCK1 (601702)/ROCK2 (604002) and MRCK-alpha (CDC42BPA; 603412), which are effectors of small RHO GTPases (see ARHA; 165390) implicated in neoplastic progression.

Some T-ALL cells show resistance to gamma-secretase inhibitors, which act by blocking NOTCH1 activation. Using microarray analysis, Palomero et al. (2007) identified PTEN (601728) as the gene most consistently downregulated in gamma-secretase inhibitor-resistant T-cell lines. Further analysis showed that these resistant cell lines had truncating mutations in the PTEN gene. Loss of PTEN function resulted in aberrant activation of the PI3-kinase (171834)-AKT (164730) signaling pathway, which induced resistance to gamma-secretase inhibitors. Studies in normal mouse thymocytes indicated that Notch1 regulated Pten expression downstream. Notch signaling and the PI3-kinase-AKT pathway acted synergistically in a Drosophila model of Notch-induced tumorigenesis. The findings demonstrated that NOTCH1 controls a transcriptional network that regulates PTEN expression and PI3-kinase-AKT signaling activity in normal thymocytes and leukemic T cells.

Mizutani et al. (2007) showed that both neural stem cells and intermediate neural progenitors respond to Notch receptor activation, but that neural stem cells signal through the canonic Notch effector C-promoter binding factor (CBF1; 147183), whereas intermediate neural progenitors have attenuated CBF1 signaling. Furthermore, whereas knockdown of CBF1 promotes the conversion of neural stem cells to intermediate neural progenitors, activation of CBF1 is insufficient to convert intermediate neural progenitors back to neural stem cells. Using both transgenic and transient in vivo reporter assays, Mizutani et al. (2007) showed that neural stem cells and intermediate neural progenitors coexist in the telencephalic ventricular zone of mice and that they can be prospectively separated on the basis of CBF1 activity. Furthermore, using in vivo transplantation, they showed that whereas neural stem cells generate neurons, astrocytes, and oligodendrocytes at similar frequencies, intermediate neural progenitors are predominantly neurogenic. Mizutani et al. (2007) concluded that their study, together with previous work on hematopoietic stem cells, suggested the use or blockade of the CBF1 cascade downstream of Notch as a general feature distinguishing stem cells from more limited progenitors in a variety of tissues.

Sjolund et al. (2008) found that Notch signaling was constitutively active in human clear cell renal cell carcinoma (CCRCC) cell lines. Blocking Notch signaling attenuated proliferation and restrained anchorage-independent growth of CCRCC cell lines and inhibited growth of xenotransplanted CCRCC cells in nude mice. Small interfering RNA against various Notch receptors showed that growth promotion was due to Notch1 activation, and Notch1 knockdown was accompanied by elevated levels of the negative cell cycle regulators p21(Cip1) and/or p27(Kip1) (CDKN1B; 600778). Moreover, Notch1 and the Notch ligand Jagged1 were expressed at significantly higher levels in CCRCC tumors than in normal human renal tissue, and growth of primary CCRCC cells was attenuated upon inhibition of Notch signaling.

Niranjan et al. (2008) showed that genes in the Notch pathway were expressed in mature podocytes in humans and in rodent models of diabetic nephropathy and focal segmental glomerulosclerosis. In vitro and in vivo studies showed that the Notch intracellular domain induced apoptosis of podocytes, and genetic or pharmacologic inhibition of the Notch pathway protected rats with proteinuric kidney diseases.

Moellering et al. (2009) reported the design of synthetic, cell-permeable, stabilized alpha-helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex. The authors demonstrated that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 (stapled alpha-helical peptide derived from MAML1, 605424) prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-ALL. The treatment of leukemic cells with SAHM1 resulted in genomewide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program caused potent, NOTCH-specific antiproliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL.

Ligand binding in Notch receptors triggers a conformational change in the receptor-negative regulatory region (NRR) that enables ADAM (see 601533) protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalyzed by the gamma-secretase complex liberates the intracellular domain to initiate downstream Notch transcriptional program. Aberrant signaling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for drugs (summary by Wu et al., 2010). Although gamma-secretase inhibitors (GSIs) had progressed into the clinic, GSIs failed to distinguish individual Notch receptors, inhibited other signaling pathways, and caused intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (Riccio et al., 2008). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, Wu et al. (2010) used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralog and yet crossreact with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. The cocrystal structure showed that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibited tumor growth in preclinical models through 2 mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors.

Engel et al. (2010) found that Mtg16 (CBFA2T3; 603870) -/- mouse hematopoietic progenitor cells showed elevated expression of Notch targets, in addition to impaired differentiation, in response to Notch signaling. The defect was reversed by restoration of Mtg16 expression. Using mouse and human cells, Engel et al. (2010) showed that all MTG family proteins bound CSL and that MTG16 bound the ICDs of all Notch receptor proteins. Binding of MTG16 to Notch ICD disrupted MTG16-CSL and MTG16-NCOR (see 600849) interactions and permitted Notch signaling. Mutation and coprecipitation analysis revealed that the N-terminal PST region of MTG16 interacted directly with Notch ICD and that binding was independent of the MTG16 NTR domains required for DNA, CSL, and histone deacetylase binding. The PST region of Mtg16 was also essential for Mtg16-dependent lineage specification in mouse hematopoietic progenitor cells. Engel et al. (2010) concluded that MTG16 is an integral component of Notch signaling that contributes to basal repression of canonical Notch target genes.

Guarani et al. (2011) reported that the NAD(+)-dependent deacetylase SIRT1 (604479) acts as an intrinsic negative modulator of Notch signaling in endothelial cells. They showed that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with the NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signaling, resulting in impaired growth, sprout elongation, and enhanced Notch target gene expression in response to DLL4 (605185) stimulation, thereby promoting a nonsprouting, stalk cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signaling. Guarani et al. (2011) concluded that their findings identified reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signaling, and indicated that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.

Rios et al. (2011) characterized the signaling events taking place during morphogenesis of chick skeletal muscle and showed that muscle progenitors present in somites require the transient activation of NOTCH signaling to undergo terminal differentiation. The NOTCH ligand Delta1 (606582) is expressed in a mosaic pattern in neural crest cells that migrate past the somites. Gain and loss of Delta1 function in neural crest modifies NOTCH signaling in somites, which results in delayed or premature myogenesis. Rios et al. (2011) concluded that the neural crest regulates early muscle formation by a unique mechanism that relies on the migration of Delta1-expressing neural crest cells to trigger the transient activation of NOTCH signaling in selected muscle progenitors. This dynamic signaling guarantees a balanced and progressive differentiation of the muscle progenitor pool.

Using yeast 2-hybrid and immunoprecipitation assays, Sanchez-Solana et al. (2011) showed that DLK1 (176290) and DLK2 (621120) interacted with themselves and with each other through their extracellular EGF-like regions to form homodimers and heterodimers. DLK1 and DLK2 also interacted with NOTCH1 through their extracellular regions. By interacting with NOTCH1, DLK1 and DLK2 inhibited NOTCH activation and signaling by competing with the NOTCH1-activating ligands DLL4 and JAGGED1 for NOTCH1 binding.

Nueda et al. (2018) found that overexpression of any of the 4 Notch receptors enhanced adipogenesis of 3T3-L1 preadipocytes. Further analysis showed that Dlk1 and Dlk2 inhibited activity of all 4 Notch receptors to different degrees. Overexpression of Notch1 stimulated differentiation of 3T3-L1 cells towards a brown-like adipocyte phenotype, whereas overexpression of Notch2 (600275), Notch3 (600276), or Notch4 (164951), or of Dlk1 or Dlk2, promoted differentiation towards a white-like adipocyte phenotype. The authors observed a complex feedback mechanism involving the Notch and Dlk genes in regulation of their expression.

Moretti et al. (2012) stated that ITCH (606409) polyubiquitinates nonactivated membrane-anchored Notch receptor and targets Notch for lysosomal degradation. Using an inhibitor of lysosomal proteases, Moretti et al. (2012) confirmed that nonactivated Notch is degraded via the lysosome. Using mouse and human cells and constructs, they found that the deubiquitinating enzyme USP12 (603091) interacted with ITCH and with UAF1 (WDR48; 612167). The USP12-UAF1 complex deubiquitinated nonactivated Notch and was required for Notch degradation in lysosomes. Knockdown of USP12 or UAF1, or overexpression of inactive USP12, resulted in accumulation of Notch receptor in endosomes. Moretti et al. (2012) proposed a model whereby USP12-UAF1 is recruited to Notch-Itch, resulting in proper trafficking of Notch receptor to lysosomes.

Using immunoprecipitation analysis, Puca et al. (2013) showed that human ARRDC1 (619768) interacted directly with ITCH. Simultaneously, ARRDC1 interacted directly with beta-arrestin-1 (ARRB1; 107940) and beta-arrestin-2 (ARRB2; 107941) to form a complex that recruited ITCH to NOTCH. Through these interactions, ARRDC1 was involved in ITCH-mediated NOTCH ubiquitylation and lysosomal degradation at the same step, but not redundantly, with the beta-arrestins. Moreover, ARRDC1 and the beta-arrestins acted as negative regulators of NOTCH signaling as members of the same complex.

Kasahara et al. (2013) found that interruption of mitochondrial fusion disrupts the calcium/calcineurin (see 114105) pathway that regulates the central cardiac development factor Notch1, interrupting cardiomyocyte proliferation and blocking fetal cardiac development. Ablation of mitochondrial fusion proteins mitofusin-1 (Mfn1; 608506) and -2 (Mfn2; 608507) in the embryonic mouse heart, or gene trapping of Mfn2 or optic atrophy-1 (Opa1; 605290) in mouse embryonic stem cells, arrested mouse heart development and impaired differentiation of embryonic stem cells into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors Tgf-beta (190180)/Bmp (see 112264), serum response factor (SRF; 600589), Gata4 (600576), and myocyte enhancer factor-2 (see 600660), linked to increased calcium-dependent calcineurin activity and Notch1 signaling that impaired embryonic stem cell differentiation. Kasahara et al. (2013) concluded that orchestration of cardiomyocyte differentiation by mitochondrial morphology revealed how mitochondria, calcium, and calcineurin interact to regulate Notch1 signaling.

Magnusson et al. (2014) reported that stroke elicits a latent neurogenic program in striatal astrocytes in mice. Notch1 signaling is reduced in astrocytes after stroke, and attenuated Notch1 signaling is necessary for neurogenesis by striatal astrocytes. Blocking Notch signaling triggers astrocytes in the striatum and medial cortex to enter a neurogenic program, even in the absence of stroke, resulting in 850 +/- 210 (mean +/- SEM) new neurons in a mouse striatum. Magnusson et al. (2014) concluded that under Notch signaling regulation, astrocytes in adult mouse parenchyma carry a latent neurogenic program that could be useful for neuronal replacement strategies.

By purifying NOTCH complexes from NOTCH-induced human T-cell lymphomas, followed by coimmunoprecipitation analysis, Weaver et al. (2014) identified PRAG1 (617344), which they called NACK, as a NOTCH-interacting protein. Fractionation experiments showed colocalization of PRAG1 and NOTCH1 in nucleus. Beta-galactosidase staining of transgenic knockin mice revealed coexpression of Prag1 and Notch1 in central nervous system of embryonic day-12.5 (E12.5) and E16.5 mouse embryos. Pull-down experiments showed that binding of PRAG1 to the NOTCH complex on DNA depended on binding of the complex to CSL and MAML1. Mutations in NOTCH1 or MAML1 that inhibited NOTCH complex transcriptional activity inhibited binding of PRAG1 to the complex on DNA. Cotransfection of PRAG1 with the NOTCH1 ICD in H1299 human lung carcinoma cells increased CSL-directed transcription, similar to the effect of cotransfection of MAML1 with the NOTCH1 ICD. Chromatin immunoprecipitation analysis of OE33 human esophageal adenocarcinoma cells, which are dependent on NOTCH activity, showed that PRAG1-NOTCH complexes specifically localized to the promoter region of the NOTCH target HES1. Knockdown of PRAG1 using short hairpin RNA resulted in decreased HES1 expression in OE33 cells and attenuation of NOTCH-induced Hes1 expression in HC11 mouse mammary epithelial cells. Expression of Prag1 was upregulated following expression of the ICD of any NOTCH family member in mouse embryonic fibroblasts, which lack endogenous NOTCH activity. Chromatin immunoprecipitation analysis showed binding of NOTCH to the PRAG1 promoter. Immunohistochemical and quantitative RT-PCR analyses of clinical samples of surgically resected pancreatic ductal adenocarcinoma and esophageal adenocarcinoma showed higher levels of PRAG1 and NOTCH compared with normal tissue, and this increased expression was also seen in pancreatic ductal adenocarcinoma by immunohistochemical analysis. Knockdown of Prag1 reduced anchorage-independent growth on soft agar in HC11 cells infected with NOTCH1 ICD. Furthermore, knockdown of PRAG1 in human esophageal adenocarcinoma cells prior to injection of cells into nude mice resulted in decreased tumor growth. Weaver et al. (2014) concluded that PRAG1 is an essential component of the NOTCH complex that regulates NOTCH-mediated tumorigenesis and development.

Taniguchi et al. (2015) showed in mice and human cells that GP130 (600694), a coreceptor for IL6 (147620) cytokines, triggers activation of YAP (606608) and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the GP130 effector STAT3 (102582). Through YAP and Notch, intestinal GP130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation, and confers resistance to mucosal erosion. GP130 associates with the related tyrosine kinases SRC (190090) and YES (164880), which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

Using an engineered organotypic model of perfused microvessels, Polacheck et al. (2017) showed that activation of the transmembrane receptor NOTCH1 directly regulates vascular barrier function through a noncanonical, transcription-independent signaling mechanism that drives assembly of adherens junctions. They confirmed these findings in mouse models. Shear stress triggers DLL4 (605185)-dependent proteolytic activation of NOTCH1 to expose the transmembrane domain of NOTCH1. This domain mediates establishment of the endothelial barrier; expression of the transmembrane domain of NOTCH1 is sufficient to rescue defects in barrier function induced by knockout of NOTCH1. The transmembrane domain restores barrier function by catalyzing the formation of a receptor complex in the plasma membrane consisting of vascular endothelial cadherin (CDH5; 601120), the transmembrane protein tyrosine phosphatase LAR (PTPRF; 179590), and the RAC1 guanidine-exchange factor TRIO (601893). This complex activates RAC1 (602048) to drive assembly of adherens junctions and establish barrier function. Canonical transcriptional signaling via Notch is highly conserved in metazoans and is required for many processes in vascular development, including arterial-venous differentiation, angiogenesis, and remodeling. Polacheck et al. (2017) concluded that they established the existence of a noncanonical cortical NOTCH1 signaling pathway that regulates vascular barrier function, and thus provided a mechanism by which a single receptor might link transcriptional programs with adhesive and cytoskeletal remodeling.

Lim et al. (2017) showed that Notch signaling can be both tumor suppressive and protumorigenic in small cell lung cancer (see 182280). Endogenous activation of the Notch pathway results in a neuroendocrine to nonneuroendocrine fate switch in 10 to 50% of tumor cells in a mouse model of small cell lung cancer and in human tumors. This switch is mediated in part by Rest (600571), a transcriptional repressor that inhibits neuroendocrine gene expression. Nonneuroendocrine Notch-active small cell lung cancer cells are slow growing, consistent with a tumor-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumor cells, consistent with a protumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumor growth and delays relapse in preclinical models. Lim et al. (2017) concluded that thus, small cell lung cancer tumors generate their own microenvironment via activation of Notch signaling in a subset of tumor cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small cell lung cancer.

Loganathan et al. (2020) focused on 484 genes harboring recurrent but rare mutations ('long tail' genes) in head and neck squamous cell carcinoma (HNSCC; 275355) and used in vivo CRISPR to screen for genes that, upon mutation, trigger tumor development in mice. Of the 15 tumor-suppressor genes identified, ADAM10 (602192) and AJUBA (609066) suppressed HNSCC in a haploinsufficient manner by promoting NOTCH receptor signaling. ADAM10 and AJUBA mutations or monoallelic loss occurred in 28% of human HNSCC cases and were mutually exclusive with NOTCH receptor mutations. Loganathan et al. (2020) concluded that their results showed that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of this cancer.

Role of Notch in Early Embryonic Development

Takahashi et al. (2000) found that Mesp2 (605195) initiates the establishment of rostro-caudal polarity by controlling 2 Notch signaling pathways. Initially, Mesp2 activates a Ps1-independent Notch signaling cascade to suppress Dll1 (see 602768) expression and specify the rostral half of the somite. Ps1-mediated Notch signaling is required to induce Dll1 expression in the caudal half of the somite. Therefore, Mesp2- and Ps1-dependent activation of Notch signaling pathways might differentially regulate Dll1 expression, resulting in the establishment of the rostro-caudal polarity of somites.

Using mouse embryos with deficient Notch signaling, Morales et al. (2002) showed that dynamic expression of the mouse Lfng gene in the cycling presomitic mesoderm (PSM) is lost in the absence of Notch signaling. They concluded that periodic Lfng expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to Notch signaling.

Dale et al. (2003) demonstrated that the protein product of Lfng, which encodes a glycosyltransferase that can modify Notch activity, oscillates in the chick presomitic mesoderm. Overexpressing Lfng in the paraxial mesoderm abolishes the expression of cyclic genes including endogenous Lfng and leads to defects in segmentation. This effect on cyclic genes phenocopies inhibition of Notch signaling in the presomitic mesoderm. Dale et al. (2003) therefore proposed that Lfng establishes a negative feedback loop that implements periodic inhibition of Notch, which in turn controls rhythmic expression of cyclic genes in the chick presomitic mesoderm. This feedback loop provides a molecular basis for the oscillator underlying the avian segmentation clock.

Raya et al. (2004) first investigated whether Notch activity is necessary for establishing proper left-right asymmetry during chick embryo development. Blocking the Notch signaling pathway by overexpressing a dominant-negative form of the Notch pathway effector RBPSUH resulted in laterality defects at both the morphologic and molecular levels similar to those described for mouse embryos. Raya et al. (2004) found that before the appearance of the left-sided perinodal expression domain of Nodal (601265), the Notch ligands Dll1 and Serrate1 showed complementary patterns of expression that form a sharp anterior/posterior interface across the Hensen node. During HH3 to HH7 stages of chick embryo development, Lfng is expressed in a complex, dynamic pattern of waves that sweep the AP axis of the embryo. Raya et al. (2004) noticed that the fifth wave of Lfng is clearly asymmetric when it reaches the node at HH6: the medial-most part of the left stripe is anteriorly displaced with respect to the right. Raya et al. (2004) developed a mathematical model which described the dynamics of the Notch signaling pathway during chick embryo gastrulation, which revealed a complex and highly robust genetic network that locally activates Notch on the left side of the Hensen node. Raya et al. (2004) identified the source of the asymmetric activation of Notch as a transient accumulation of extracellular calcium, which in turn depends on left-right differences in hydrogen/potassium-ATPase activity. Raya et al. (2004) concluded that their results uncovered a mechanism by which the Notch signaling pathway translates asymmetry in epigenetic factors into asymmetric gene expression around the node.

Morimoto et al. (2005) visualized endogenous levels of Notch1 activity in mice, showing that it oscillates in the posterior presomitic mesoderm but is arrested in the anterior presomitic mesoderm. Somite boundaries formed at the interface between Notch1-activated and -repressed domains. Genetic and biochemical studies indicated that this interface is generated by suppression of Notch activity by Mesp2 through induction of the Lfng gene. Morimoto et al. (2005) proposed that the oscillation of Notch activity is arrested and translated in the wavefront by Mesp2.

Boskovski et al. (2013) showed, in Xenopus tropicalis, that GALNT11 (615130) activates Notch signaling. GALNT11 O-glycosylated human NOTCH1 peptides in vitro, thereby supporting a mechanism of Notch activation either by increasing ADAM17 (603639)-mediated ectodomain shedding of the Notch receptor or by modification of specific EGF repeats. Boskovski et al. (2013) developed a quantitative live imaging technique for Xenopus left-right organizer cilia and showed that GALNT11-mediated NOTCH1 signaling modulates the spatial distribution and ratio of motile and immotile cilia at the left-right organizer. GALNT11 or NOTCH1 depletion increases the ratio of motile cilia at the expense of immotile cilia and produces a laterality defect reminiscent of loss of the ciliary sensor PKD2 (173910). By contrast, Notch overexpression decreases this ratio, mimicking the ciliopathy primary ciliary dyskinesia-1 (CILD1; 244400). Boskovski et al. (2013) concluded that their data demonstrated that GALNT11 modifies Notch, establishing an essential balance between motile and immotile cilia at the left-right organizer to determine laterality, and revealed a novel mechanism for human heterotaxy.

Del Monte-Nieto et al. (2018) presented a model of trabeculation in mice that integrated dynamic endocardial and myocardial cell behaviors and extracellular matrix (ECM) remodeling, and revealed epistatic relationships between the involved signaling pathways. Notch1 signaling promotes extracellular matrix degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas Nrg1 (142445) promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through Nrg1 control of Vegfa (192240), but act antagonistically to establish trabecular architecture. Del Monte-Nieto et al. (2018) concluded that their findings enabled the prediction of persistent extracellular matrix and cardiomyocyte growth in a mouse noncompaction cardiomyopathy model, providing insights into the pathophysiology of congenital heart disease.

Role of Notch in Cell Fate Determination

Tanigaki et al. (2001) presented evidence that activated NOTCH1 and NOTCH3 promote the differentiation of astroglia from rat adult hippocampus-derived multipotent progenitors. Transient activation of Notch can direct commitment of adult hippocampal-derived progenitors irreversibly to astroglia. Astroglial induction by Notch signaling was shown to be independent of STAT3 (102582), which is a key regulatory transcriptional factor when ciliary neurotrophic factor (CNTF; 118945) induces astroglia. Tanigaki et al. (2001) suggested that Notch provides a CNTF-independent instructive signal of astroglia differentiation in central nervous system multipotent progenitor cells.

Shen et al. (2004) demonstrated that endothelial cells but not vascular smooth muscle cells release soluble factors that stimulate the self-renewal of neural stem cells, inhibit their differentiation, and enhance their neuron production. Both embryonic and adult neural stem cells respond, allowing extensive production of both projection neuron and interneuron types in vitro. Endothelial coculture stimulated neuroepithelial cell contact, activating Notch and HES1 (139605) to promote self-renewal. These findings identified endothelial cells as a critical component of the neural stem cell niche.

Loomes et al. (2002) characterized Notch receptor expression in the developing mouse heart and liver, 2 organs significantly affected in Alagille syndrome (see 118450). In the developing mouse heart, both Notch1 and Notch2 are expressed in the outflow tracts and the epicardium, and in specific cell populations previously shown to express Jag1 (Loomes et al., 1999). These cells are destined to undergo transformation from epithelial to mesenchymal cells. In the newborn mouse liver, Notch2 and Notch3 are expressed in opposing cell populations, suggesting they play different roles in cell fate determination during bile duct development. Jag1 is also expressed in cells adjacent to those expressing Notch2, suggesting a possible ligand-receptor interaction.

Hematopoietic stem cells (HSCs) have the ability to renew themselves and to give rise to all lineages of the blood. Reya et al. (2003) showed that the WNT signaling pathway has an important role in this process. Overexpression of activated beta-catenin (116806) expands the pool of HSCs in long-term cultures by both phenotype and function. Furthermore, HSCs in their normal microenvironment activate a LEF1/TCF (153245) reporter, which indicates that HSCs respond to WNT signaling in vivo. To demonstrate the physiologic significance of this pathway for HSC proliferation, Reya et al. (2003) showed that the ectopic expression of axin (603816) or a frizzled (603408) ligand-binding domain, inhibitors of the WNT signaling pathway, led to inhibition of HSC growth in vitro and reduced reconstitution in vivo. Furthermore, activation of WNT signaling in HSCs induced increased expression of HOXB4 (142965) and NOTCH1, genes previously implicated in self-renewal of HSCs. Reya et al. (2003) concluded that the WNT signaling pathway is critical for normal HSC homeostasis in vitro and in vivo, and provide insight into a potential molecular hierarchy of regulation of HSC development.

Murtaugh et al. (2003) found that misexpression of activated Notch in Pdx1 (IPF1; 600733)-expressing mouse pancreatic progenitor cells prevented the differentiation of both exocrine and endocrine cell lineages. Progenitors remained trapped in an undifferentiated state even if Notch activation occurred after the pancreatic fate had been specified. Endocrine differentiation was associated with escape from Notch activity.

Using immunoprecipitation and fluorescence microscopy, Hu et al. (2003) identified mouse F3 (CNTN1; 600016) as a physiologic ligand and activator of Notch. Upon activation by F3, Notch signals through Dtx1 (602582), which leads to oligodendrocyte maturation via upregulation of certain myelin-related proteins. Thus, Hu et al. (2003) concluded that Notch does not solely function to inhibit oligodendrocyte precursor differentiation to mature cells, and they suggested that it may be useful in promoting remyelination in degenerative diseases.

Okuyama et al. (2004) found that pure keratinocytes cultured from embryonic day-15.5 mouse embryos committed irreversibly to differentiation much earlier than those cultured from newborn mice. Notch signaling, which promotes keratinocyte differentiation, was upregulated in embryonic keratinocytes and epidermis, and elevated caspase-3 (600636) expression, which the authors identified as a target for Notch1 transcriptional activation, accounted in part for the high commitment of embryonic keratinocytes to terminal differentiation.

Van Es et al. (2005) showed a rapid, massive conversion of proliferative crypt cells into postmitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J (147183). The authors obtained a similar phenotype by blocking the Notch cascade with a gamma-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumor suppressor gene (611731). Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades.

By modulating Notch activity in the mouse intestine, Fre et al. (2005) directly implicated Notch signals in intestinal cell lineage specification. Fre et al. (2005) also showed that Notch activation is capable of amplifying the intestinal progenitor pool while inhibiting cell differentiation. The authors concluded that Notch activity is required for the maintenance of proliferating crypt cells in the intestinal epithelium.

Stanger et al. (2005) found that ectopic expression of Notch in adult mouse intestinal progenitor cells biased differentiation against secretory fates, whereas ectopic Notch activation in the embryonic foregut resulted in reversible defects in villus morphogenesis and loss of proliferative progenitor compartment. Stanger et al. (2005) concluded that Notch regulates adult intestinal development by controlling the balance between secretory and absorptive cell types.

RBPJ functions immediately downstream of Notch signaling. Han et al. (2002) used a conditional gene knockout strategy to inactivate the DNA-binding domain of Rbpj in mouse bone marrow and found that Rbpj was required for T-cell development. In the absence of Rbpj, there was an increase in thymic B-cell development. Han et al. (2002) proposed that RBPJ-mediated Notch signaling controls T- versus B-cell fate decisions in lymphoid progenitors.

Thymocytes can be divided into 4 subsets based on CD4 (186940) and CD8 (see 186910) expression, with double-negative (DN) cells being the least mature. The DN population can be further subdivided into 4 subsets, DN1 through DN4. Tanigaki et al. (2004) used a conditional knockout strategy to inactivate Rbpj at the DN2 and DN4 stages in mice. Inactivation at DN2 resulted in severe developmental arrest of alpha-beta T cells at the DN3 stage and enhanced generation of gamma-delta T cells. Inactivation at DN4 caused no abnormalities in CD4/CD8 lineage commitment, but it resulted in enhanced Th1 responses and reduced T-cell proliferation. Tanigaki et al. (2004) concluded that Notch/RBPJ signaling regulates not only the T-cell developmental process, but also the direction and magnitude of immune responses via regulation of peripheral T cells.

Using Lrf (ZBTB7; 605878) -/- mice and Lrf conditional knockout mice, Maeda et al. (2007) showed that LRF acts as a master regulator in determination of B versus T lymphoid fate by negatively regulating T-lineage commitment by opposing NOTCH function. Thus, loss of LRF results in aberrant activation of the NOTCH pathway, with upregulation of NOTCH target genes in hematopoietic stem cells and common lymphoid progenitors.

Gustafsson et al. (2005) found that hypoxia blocked differentiation of mammalian neuronal and myogenic progenitor cells in culture through a Notch signaling pathway. Hypoxia led to recruitment of Hif1a (603348) to Notch-responsive promoters and elevated expression of Notch downstream genes.

Hellstrom et al. (2007) presented evidence that Dll4 (605185)-Notch1 signaling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in mouse retina. They showed that inhibition of Notch signaling using gamma-secretase inhibitors, genetic inactivation of 1 allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1 all promoted increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 (601920) peptide led to fewer tip cells and vessel branches. Dll4 and reporters of Notch signaling were distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assumed tip cell characteristics. Hellstrom et al. (2007) concluded that DLL4 (605185)-Notch1 signaling between the endothelial cells within the angiogenic sprout restricts tip cell formation in response to VEGF (192240), thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. The authors further concluded that their model offered an explanation for the dose-dependency and haploinsufficiency of the DLL4 gene, and indicated that modulators of DLL4 or Notch signaling, such as gamma-secretase inhibitors developed for Alzheimer disease (104300), might find usage as pharmacologic regulators of angiogenesis.

Siekmann and Lawson (2007) demonstrated that Notch signaling is necessary to restrict angiogenic cell behavior to tip cells in developing segmental arteries in the zebrafish embryo. In the absence of the Notch signaling component Rbpsuh (147183), The authors observed excessive sprouting of segmental arteries, whereas Notch activation suppressed angiogenesis. Through mosaic analysis Siekmann and Lawson (2007) found that cells lacking Rbpsuh preferentially localized to the terminal position in developing sprouts. In contrast, cells in which Notch signaling had been activated were excluded from the tip cell position. In vivo time-lapse analysis revealed that endothelial tip cells undergo a stereotypical pattern of proliferation and migration during sprouting. In the absence of Notch, nearly all sprouting endothelial cells exhibited tip cell behavior, leading to excessive numbers of cells within segmental arteries. Furthermore, Siekmann and Lawson (2007) found that Flt4 (136352) was expressed in segmental artery tip cells and became ectopically expressed throughout the sprout in the absence of Notch. Loss of Flt4 partially restored normal endothelial cell number in Rbpsuh-deficient segmental arteries. Finally, loss of the Notch ligand Dll4 also led to an increased number of endothelial cells within segmental arteries. Siekmann and Lawson (2007) concluded that their studies taken together indicated that proper specification of cell identity, position, and behavior in a developing blood vessel sprout is required for normal angiogenesis, and implicated the Notch signaling pathway in this process.

Hozumi et al. (2008) found that mice lacking Dll4 expression in thymic epithelial cells (TECs) exhibited a marked reduction of Notch1 in hematopoietic cells and a lack of Cd4 and Cd8 double- or single-positive T cells in thymus. The double-negative cell fraction also showed an absence of T-cell progenitors and an aberrant accumulation of B-lineage cells. Enforced expression of the intracellular fragment of Notch1 restored thymic T-cell differentiation. Hozumi et al. (2008) concluded that the thymus-specific environment for T-cell fate determination requires DLL4 expression to induce NOTCH signaling in cells immigrating into thymus.

Using immunohistochemical analysis, Koch et al. (2008) demonstrated expression of Dll4, but not Dll1 (606582), on TECs in mice. Inactivation of Dll4 in TECs or hematopoietic progenitors in mice resulted in loss of T-cell development with no loss of thymus development, as well as ectopic appearance of immature B cells in thymus. These immature B cells were phenotypically indistinguishable from those developing in the thymus of conditional Notch1-deficient mice. Koch et al. (2008) concluded that DLL4 is the essential and nonredundant Notch1 ligand responsible for T-cell fate specification. They proposed that NOTCH1-expressing thymic progenitors interact with DLL4-expressing TECs to suppress B-lineage potential and to induce the first steps of intrathymic T-cell development.

To investigate how Delta (see 606582) both transactivates Notch neighboring cells and cis-inhibits Notch in its own cell, Sprinzak et al. (2010) developed a quantitative time-lapse microscopy platform for analyzing Notch-Delta signaling dynamics in individual mammalian cells. By controlling both cis- and trans-Delta concentrations, and monitoring the dynamics of a Notch reporter, Sprinzak et al. (2010) measured the combined cis-trans input-output relationship in the Notch-Delta system. The data revealed a striking difference between the responses of Notch to trans- and cis-Delta: whereas the response to trans-Delta is graded, the response to cis-Delta is sharp and occurs at a fixed threshold, independent of trans-Delta. Sprinzak et al. (2010) developed a simple mathematical model that shows how these behaviors emerge from the mutual inactivation of Notch and Delta proteins in the same cell. This interaction generates an ultrasensitive switch between mutually exclusive sending (high Delta/low Notch) and receiving (high Notch/low Delta) signaling states. At the multicellular level, this switch can amplify small differences between neighboring cells even without transcription-mediated feedback. Sprinzak et al. (2010) concluded that this Notch-Delta signaling switch facilitates the formation of sharp boundaries and lateral-inhibition patterns in models of development, and provides insight into previously unexplained mutant behaviors.

Aguirre et al. (2010) demonstrated that functional cell-cell interaction between neural progenitor cells (NPCs) and neural stem cells (NSCs) through EGFR (131550) and Notch signaling has a crucial role in maintaining the balance between these cell populations in the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. Enhanced EGFR signaling in vivo results in the expansion of the NPC pool and reduces NSC number and self-renewal. This occurs through a non-cell-autonomous mechanism involving EGFR-mediated regulation of Notch signaling. Aguirre et al. (2010) concluded that their findings defined a novel interaction between EGFR and Notch pathways in the adult subventricular zone, and thus provided a mechanism for NSC and NPC pool maintenance.

Benedito et al. (2012) used inducible loss-of-function genetics in combination with inhibitors in vivo to demonstrate that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 (191306) signaling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGFA receptor and is considered to be indispensable for these processes. By contrast, VEGFR3 (136352), the main receptor for VEGFC (601528), was strongly modulated by Notch. VEGFR3 kinase activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signaling activity. Benedito et al. (2012) concluded that their results established that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. They proposed that successful antiangiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signaling.

Role of Notch in Neural Development

The exuberant growth of neurites during development becomes markedly reduced as cortical neurons mature. Using in vitro studies of neurons from mouse cerebral cortex, Sestan et al. (1999) demonstrated that contact-mediated Notch signaling regulates the capacity of neurons to extend and elaborate neurites. Upregulation of Notch activity was concomitant with an increase in the number of interneuronal contacts and cessation of neurite growth. In neurons with low Notch activity, which readily extend neurites, upregulation of Notch activity either inhibited extension or caused retraction of neurites. Conversely, in more mature neurons that had ceased their growth after establishing numerous connections and displayed high Notch activity, inhibition of Notch signaling promoted neurite extension. Thus, Sestan et al. (1999) concluded that the formation of neuronal contacts results in activation of Notch receptors, leading to restriction of neuronal growth and a subsequent arrest in maturity.

Role of Notch in Muscle Regeneration

Conboy et al. (2003) analyzed injured muscle and observed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient upregulation of the Notch ligand Delta and thus diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Conboy et al. (2003) concluded that Notch signaling is a key determinant of muscle regenerative potential that declines with age.

In experiments using mouse muscle, Carlson et al. (2008) found that, in addition to the loss of Notch activation, old muscle produces excessive TGF-beta (190180) (but not myostatin, 601788), which induces unusually high levels of Smad3 (603109) in resident satellite cells and interfered with the regenerative capacity. Importantly, endogenous Notch and Smad3 antagonize each other in the control of satellite cell proliferation, such that activation of Notch blocks the TGF-beta-dependent upregulation of the cyclin-dependent kinase (CDK) inhibitors p15 (600431), p16 (600160), p21 (116899), and p27 (600778), whereas inhibition of Notch induces them. Furthermore, in muscle stem cells, Notch activity determined the binding of Smad3 to the promoters of these negative regulators of cell cycle progression. Attenuation of TGF-beta/Smad3 in old, injured muscle restored regeneration to satellite cells in vivo. Thus, a balance between endogenous Smad3 and active Notch controls the regenerative competence of muscle stem cells, and deregulation of this balance in the old muscle microniche interferes with regeneration.

Role of Notch in Bone Homeostasis

Independently, Engin et al. (2008) and Hilton et al. (2008) investigated the role of Notch signaling in bone homeostasis using rodent models. Engin et al. (2008) found that Notch and presenilin signaling regulated both osteoclastogenesis and osteoblastic proliferation. Gain of Notch function resulted in severe osteosclerosis, whereas loss of Notch function led to age-related osteoporosis. Hilton et al. (2008) found that Notch signaling in bone marrow maintained a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Disruption of Notch signaling in limb skeletogenic mesenchyme increased trabecular bone mass in adolescent mice and led to severe osteopenia as they aged.

Engin et al. (2009) reported that human osteosarcoma (259500) cell lines and primary human osteosarcoma tumor samples showed significant upregulation of Notch, its target genes, and Osterix (SP7; 606633). Notch inhibition by gamma-secretase inhibitors or by lentiviral-mediated expression of dominant-negative MAML1 protein (605424) decreased osteosarcoma cell proliferation in vitro. Established human tumor xenografts in nude mice showed decreased tumor growth after chemical or genetic inhibition of Notch signaling. Transcriptional profiling of osteosarcomas from p53 (191170) mutant mice confirmed upregulation of Notch target genes Hes1 (139605), Hey1 (602953), and its ligand Dll4 (605185). Engin et al. (2009) suggested that activation of Notch signaling may contribute to the pathogenesis of human osteosarcomas.

▼ Cytogenetics

Chromosome 7q34-q35, which contains the locus for the beta T-cell receptor (see 186930), is a common site for translocation in T-cell neoplasms. In t(7;9)(q34;q34.3) translocations from 3 cases of acute T-cell lymphoblastic leukemia, Ellisen et al. (1991) found breakpoints within 100 bp of an intron in TAN1, resulting in truncation of TAN1 transcripts. They concluded that TAN1 is important for normal lymphocyte function and that alterations in TAN1 play a role in the pathogenesis of some T-cell neoplasms.

▼ Molecular Genetics

Aortic Valve Disease

Garg et al. (2005) showed that mutations in the signaling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification (AOVD1; 109730) in nonsyndromic autosomal dominant human pedigrees (see 190198.0001-190198.0002). Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2 (600211), a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors, which are activated by Notch1 signaling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independently of histone deacetylase activity. Garg et al. (2005) concluded that their results suggested that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later derepression of calcium deposition that causes progressive aortic valve disease.

In a cohort of 48 sporadic German patients with bicuspid aortic valve (BAV), Mohamed et al. (2006) sequenced the NOTCH1 gene and identified 2 men with BAV and thoracic aortic aneurysm (AAT) who were heterozygous for missense mutations (T596M, 190198.0011 and P1797H, 190198.0012).

McBride et al. (2008) analyzed the NOTCH1 gene in 91 unrelated European American patients with congenital aortic valve stenosis, bicuspid aortic valve, coarctation of the aorta (COA; see 120000), and/or hypoplastic left heart syndrome (see 241550), and identified 2 heterozygous missense variants in 6 probands, respectively, that were either completely absent or significantly underrepresented in over 200 ethnically matched controls and were also shown to reduce ligand-induced NOTCH1 signaling. Four of the mutation-positive probands had aortic valve stenosis and/or bicuspid aortic valve, which in 1 patient was associated with COA, and 2 probands had HLHS. In each case, the NOTCH1 variant was also present in an unaffected parent; McBride et al. (2008) suggested that these variants represent susceptibility alleles that are not sufficient in and of themselves to perturb cardiac development.

Other Cardiac Malformations

Kerstjens-Frederikse et al. (2016) sequenced NOTCH1 in 428 probands with nonsyndromic left-sided congenital heart disease. Family history was obtained for all. When a mutation was detected, relatives were also tested. In 148 of the probands (35%), left-sided congenital heart disease was familial. Fourteen mutations (3%) (5 splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 of 148 familial cases (7%) and 3 of 280 sporadic disease cases (1%). Familial screening showed 49 additional mutation carriers among the 14 families, of whom 12 (25%) were asymptomatic. Most of the mutation carriers had left-sided heart disease, but 9 (18%) had right-sided or conotruncal heart disease. Thoracic aortic aneurysms occurred in 6 mutations carriers. Penetrance was high; cardiovascular malformation was found in 75% of NOTCH1 mutation carriers.

Adams-Oliver Syndrome 5

In affected individuals from 5 unrelated families with Adams-Oliver syndrome-5 (AOS5; 616028), Stittrich et al. (2014) identified heterozygosity for 5 different mutations in the NOTCH1 gene, including an 85-kb deletion spanning the NOTCH1 5-prime region (190198.0003), a splice site mutation (190198.0004), and 3 missense mutations (C429R, 190198.0005; C1496Y, 190198.0006; D1989N, 190198.0007).

In 11 (17%) of 64 probands with AOS, Southgate et al. (2015) identified mutations in the NOTCH1 gene (see, e.g., 190198.0008 and 190198.0010) and concluded that NOTCH1 is the primary cause of Adams-Oliver syndrome.

T-cell Acute Lymphoblastic Leukemia

Very rare cases of human T-cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T-cell development. Weng et al. (2004) reported that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. Weng et al. (2004) concluded that their findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.

Isolated Juvenile or Chronic Myelomonocytic Leukemia

Klinakis et al. (2011) identified novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukemia (CMML). Inactivation of Notch signaling in mouse hematopoietic stem cells resulted in aberrant accumulation of granulocyte/monocyte progenitors, extramedullary hematopoiesis, and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1 (139605). Klinakis et al. (2011) concluded that their studies identified a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggested that the Notch pathway can play both tumor-promoting and -suppressive roles within the same tissue.

Chronic Lymphocytic Leukemia

Puente et al. (2011) identified somatic mutations in the NOTCH1 gene in 31 (12.2%) of 255 cases of chronic lymphocytic leukemia (CLL; 151400). These mutations generated a premature stop codon, resulting in a NOTCH1 protein lacking the C-terminal domain. The mutations caused an accumulation of an active protein isoform in the mutated CLL cells, since this isoform is more stable and active. NOTCH1-mutated patients had a more advanced clinical stage at diagnosis, more adverse biological features, and an overall shorter survival than those without NOTCH1 mutations. NOTCH1-mutated CLL also underwent transformation into diffuse large B-cell lymphoma more frequently than NOTCH1-unmutated CLL (23% vs 1.3%).

Quesada et al. (2012) identified somatic mutations in the NOTCH1 gene in 25 (9.5%) of 260 cases of CLL.

Head and Neck Squamous Cell Carcinoma

To explore the genetic origins of head and neck squamous cell carcinoma (HNSCC; 275355), Agrawal et al. (2011) used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53 (191170), CDKN2A (600160), PIK3CA (171834), and HRAS (171834), Agrawal et al. (2011) identified mutations in FBXW7 (606278) and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type. Seven of 21 patients with NOTCH1 mutations had 2 independent mutations presumably on different alleles. After TP53, NOTCH1 was the most frequently mutated gene found in the combined discovery and prevalence sets, with alterations present in 15% of patients.

Stransky et al. (2011) independently analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying known HNSCC genes, their analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (i.e., NOTCH1; IRF6, 607199; and TP63, 603273), implicating its dysregulation as a major driver of HNSCC carcinogenesis.

Mutation in Normal Esophageal Epithelium

By intensively sequencing 682 microscale esophageal samples, Yokoyama et al. (2019) showed, in physiologically normal esophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with aging, and ultimately replace almost the entire esophageal epithelium in the extremely elderly. Compared with mutations in esophageal cancer (133239), there is a marked overrepresentation of NOTCH1 and PPM1D (605100) mutations in physiologically normal esophageal epithelia; these mutations can be acquired before late adolescence and as early as early infancy, and significantly increase in number with heavy smoking and drinking. The remodeling of the esophageal epithelium by driver-mutated clones is an inevitable consequence of normal aging, which, depending on lifestyle risks, may affect cancer development.

▼ Animal Model

Huppert et al. (2000) mutated valine at position 1744 of the mouse Notch1 gene to glycine. This position is the site for proteolytic cleavage and is critical for Notch1 intracellular processing in tissue-culture cells. Huppert et al. (2000) generated homozygous animals carrying 2 germline mutations and compared these with mice who have 2 null alleles for Notch1 (Conlon et al., 1995). At embryonic day 8.5 to 10.5, homozygous embryos were detected at the expected mendelian frequency. Similar to the null alleles, embryo absorption was detected between embryonic day 10 and 12, and no homozygous embryos were recovered past embryonic day 12. These results suggested that efficient Notch processing is necessary for the early embryonic developmental aspects of Notch activity. RT-PCR and immunoprecipitation showed comparable amounts of Notch mRNA and protein, respectively, in the processing-deficient embryos and their heterozygous and wildtype littermates. The phenotypes associated with the single point mutation resembled the null Notch1 phenotype, but with slightly reduced penetrance.

Krebs et al. (2000) generated Notch4 (164951)-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene (Swiatek et al., 1994). Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. Both Notch1 mutant and Notch1/Notch4 double mutant embryos displayed severe defects in angiogenic vascular remodeling. Analysis of the expression patterns of genes encoding ligands for Notch family receptors indicated that only the Dll4 (DLL4; 605185) gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. Krebs et al. (2000) stated that these results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling, and indicate that whereas the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice.

In vertebrates with mutations in the Notch cell-cell communication pathway, segmentation fails: the boundaries demarcating somites, the segments of the embryonic body axis, are absent or irregular. Somite patterning is thought to be governed by a 'clock-and-wavefront' mechanism: a biochemical oscillator (the segmentation clock) operates in the cells of the presomitic mesoderm, the immature tissue from which the somites are sequentially produced, and a wavefront of maturation sweeps back through this tissue, arresting oscillation and initiating somite differentiation. Cells arrested in different phases of their cycle express different genes, defining the spatially periodic pattern of somites and controlling the physical process of segmentation. Jiang et al. (2000) analyzed a set of zebrafish mutants and determined that the essential function of Notch signaling in somite segmentation is to keep the oscillations of neighboring presomitic mesoderm cells synchronized.

Nicolas et al. (2003) studied the role of Notch signaling in mammalian skin. Conventional gene targeting was not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1 -/- embryos die during gestation. Therefore, Nicolas et al. (2003) used a tissue-specific inducible gene targeting approach to study the physiologic role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 resulted in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and primary keratinocytes resulted in increased and sustained expression of Gli1 (165220), causing the development of basal cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis resulted in derepressed beta-catenin (CTNNB1; 116806) signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling could be reversed by reintroduction of a dominant active form of the Notch1 receptor. The results indicated that Notch1 functions as a tumor suppressor gene in mammalian skin.

Kumano et al. (2003) found that hematopoietic stem cell development and angiogenesis were severely impaired in paraaortic splanchnopleura (P-Sp) culture of Notch1 -/-, but not Notch2 -/-, mouse embryos. Although colony-forming cell activity in the yolk sac was unimpaired in Notch1 -/- mice, hematopoietic stem cell activity was undetectable in either the yolk sac or P-Sp culture.

Krebs et al. (2003) showed that mouse embryos mutant for the Notch ligand Dll1 or doubly mutant for Notch1 and Notch2 exhibited multiple defects in left-right asymmetry. Dll1 -/- embryos did not express Nodal in the region around the node. Analysis of the enhancer regulating node-specific Nodal expression revealed binding sites for Rbpj. Mutation of these sites destroyed the ability of the enhancer to direct node-specific gene expression in transgenic mice. Krebs et al. (2003) concluded that Dll1-mediated Notch signaling is essential for generation of left-right asymmetry, and that perinodal expression of Nodal is an essential component of left-right asymmetry determination in mice.

Using gain- and loss-of-function experiments in zebrafish and mouse, Raya et al. (2003) showed that activity of the Notch pathway was necessary and sufficient for Nodal expression around the node and for proper left-right determination. They also identified critical Rbpj-binding sequences in the Nodal promoter.

Using inducible ablation of Notch1 in adult mouse cornea, Vauclair et al. (2007) showed that Notch1 -/- corneal progenitor cells lost the ability to repair mechanically wounded corneal epithelium. Instead of generating a new cornea after injury, Notch1 -/- corneal cells repaired the wound into a hyperproliferative epidermis-like epithelium, similar to xerophthalmia caused by vitamin A deficiency. Repair was associated with secretion of Fgf2 (134920) through Notch1 -/- epithelium, followed by vascularization and remodeling of the underlying stroma. Vauclair et al. (2007) identified Crbp1 (RBP1; 180260) as a direct Notch1 target within the corneal epithelium, linking the Notch pathway to vitamin A metabolism.

Gamma-secretase inhibitors block the activation of oncogenic NOTCH1 in T-ALL, but the clinical use of these drugs in humans has been limited by antileukemic cytotoxicity and severe gastrointestinal toxicity. Real et al. (2009) found that treatment of several glucocorticoid-resistant T-ALL cell lines with a combination of gamma-secretase inhibitors and corticosteroids resulted in synergistic dose-related apoptotic cell death. The findings were specific to T-ALL. Microarray analysis of these cells indicated that inhibition of NOTCH1 resulted in upregulation of the glucocorticoid receptor NR3C1 (138040) as well as increased expression of BCL2L11 (603827). In mouse models of human T-ALL, this double treatment resulted in antileukemic effects and cell cycle arrest. In addition, the double treatment protected mice from developing intestinal goblet cell metaplasia that was typically induced by treatment with gamma-secretase inhibitors alone. Further studies indicated that upregulation of Klf4 (602252) was responsible for the metaplastic gastrointestinal effects of gamma-secretase inhibitors.

Using a mouse model of aplastic anemia (609135) and conditionally deleting Notch1 or administering gamma-secretase inhibitors (GSIs), Roderick et al. (2013) observed attenuated aplastic anemia and rescue of mice from bone marrow failure. The cleaved, active form of Notch1, which was increased in wildtype mice with aplastic anemia, bound to the Tbx21 (604895) promoter, and these findings were also detected in humans with untreated aplastic anemia. Extended GSI treatment had no adverse effect on engraftment or long-term hematopoiesis, and it also resulted in loss of Notch1 binding to the Tbx21 promoter. Roderick et al. (2013) concluded that NOTCH1 is a critical mediator of Th1 pathology in aplastic anemia through its direct regulation of TBX21 and that NOTCH1 is responsive to GSIs in vitro and in vivo.

▼ ALLELIC VARIANTS ( 12 Selected Examples):

Table View ClinVar

.0001 AORTIC VALVE DISEASE 1

NOTCH1, ARG1108TER

RCV000013294...

In a 5-generation pedigree affected by autosomal dominant congenital heart disease and valve calcification (AOVD1; 109730), Garg et al. (2005) identified a C-to-T transition at nucleotide 3322 of the NOTCH1 gene that resulted in an arg-to-ter substitution at codon 1108 (R1108X), in the extracellular domain. Affected family members had aortic stenosis, dysmorphic aortic valve, ventricular septal defect, tetralogy of Fallot, and mitral stenosis with or without bicuspid aortic valve and calcification. Unaffected individuals manifested no valvular or other congenital heart disease.

.0002 AORTIC VALVE DISEASE 1

NOTCH1, 1-BP DEL, NT4515

RCV000013295

In a family with autosomal dominant congenital heart disease with valve calcification (AOVD1; 109730), Garg et al. (2005) identified heterozygosity for a frameshift mutation in the NOTCH1 gene at the his1505 position. The mutation was predicted to result in a severely altered protein containing 74 incorrect amino acids at the C terminus of the extracellular domain followed by a premature stop codon. Affected individuals had severe aortic stenosis, hypoplastic left ventricle, and double-outlet right ventricle with calcification and bicuspid aortic valve. The phenotype segregated with the mutation in affected family members.

.0003 ADAMS-OLIVER SYNDROME 5

NOTCH1, 85-KB DEL

RCV000144232

In a 6-year-old boy with Adams-Oliver syndrome-5 (AOS5; 616028), Stittrich et al. (2014) identified heterozygosity for a de novo 85-kb deletion involving the 5-prime region of the NOTCH1 gene, including part of the promoter and all of exon 1 (chr9:139,439,620-139,524,480; GRCh37). The deletion was not found in the unaffected parents, in 2 unaffected sibs, or in more than 10,000 control genomes or exomes. The patient had occipital aplasia cutis congenita, marked cutis marmorata, hypoplastic and dystrophic toenails, and areas of focal calcinosis cutis. Mild narrowing of the pulmonary branch arteries was noted on echocardiography in infancy; at age 6 years, the branch pulmonary arteries were normal, and there was stable dilation of the main pulmonary artery.

.0004 ADAMS-OLIVER SYNDROME 5

NOTCH1, IVS4AS, G-T, -1

RCV000144234

In a father and daughter with Adams-Oliver syndrome-5 (AOS5; 616028), Stittrich et al. (2014) identified heterozygosity for a splice site mutation in intron 4 of the NOTCH1 gene (c.743-1G-T, at chr9:139,414,018; GRCh37), disrupting the exon 5 acceptor splice site. The mutation was not found in the unaffected mother or an unaffected brother, or in more than 10,000 control genomes or exomes. The daughter had severe aplasia cutis of the scalp that was complicated by recurrent hemorrhage during a lengthy healing process. She had hypoplastic toes on the left foot and nail hypoplasia of the second and third toes. Her father was born with a cutaneous and bony defect involving two-thirds of his cranium, brachydactyly of the right hand, and terminal transverse defects of both feet, including soft-tissue syndactyly of hypoplastic toes. Bony ingrowth of the skull never fully bridged the father's cranial defect.

.0005 ADAMS-OLIVER SYNDROME 5

NOTCH1, CYS429ARG

RCV000144235

In a 14-year-old boy of Portuguese ancestry with Adams-Oliver syndrome (AOS5; 616028), originally described by Silva et al. (2012), Stittrich et al. (2014) identified heterozygosity for a de novo c.1285T-C transition (chr9:139,412,360; GRCh37) in the NOTCH1 gene, resulting in a cys429-to-arg (C429R) substitution at a highly conserved residue in calcium-binding EGF (131530)-like repeat 11. The mutation was not found in his unaffected parents or in more than 10,000 control genomes or exomes.

.0006 ADAMS-OLIVER SYNDROME 5

NOTCH1, CYS1496TYR

RCV000144236

In a female proband of European and Asian ancestry with Adams-Oliver syndrome-5 (AOS5; 616028), Stittrich et al. (2014) identified heterozygosity for a de novo c.4487G-A transition (chr9:139,399,861; GRCh37) in the NOTCH1 gene, resulting in a cys1496-to-tyr (C1496Y) substitution at a highly conserved residue within the extracellular negative regulatory region (NRR) of the second Lin-12 NOTCH repeat (LNR) domain. Stittrich et al. (2014) noted that the NRR sterically inhibits processing of NOTCH1 in the absence of ligand stimulation; thus, destabilization of this domain could increase constitutive Notch signaling and result in a gain of function. The mutation was not found in the proband's unaffected parents or in more than 10,000 control genomes or exomes. The patient was born with severe aplasia cutis affecting most of the scalp superior to the ears as well as the posterior neck. She had bilateral prominent tortuous scalp vessels, truncal cutis marmorata, and bilateral toe hypoplasia with absent toenails. Neuroimaging at day 1 of life showed small focal areas of bilateral parietal and left frontal white matter acute infarction and partial superior sagittal sinus thrombosis; repeat imaging at 1 week showed evolving biparietal and left frontal lobe infarcts, near-complete sagittal sinus thrombosis, and biparietal cortical venous thromboses, with stabilization and improvement over the next several months. She also had mild mitral valve annulus hypoplasia and multiperforated patent foramen ovale with insignificant shunting; severe pulmonary hypertension on day 1 of life resolved by day 10.

.0007 ADAMS-OLIVER SYNDROME 5

NOTCH1, ASP1989ASN

RCV000144233

In a 24-year-old woman with Adams-Oliver syndrome-5 (AOS5; 616028), originally reported by Vandersteen and Dixon (2011), Stittrich et al. (2014) identified heterozygosity for a c.5965G-A transition (chr9: 139,393,681; GRCh37) in the NOTCH1 gene, resulting in an asp1989-to-asn (D1989N) substitution at a highly conserved residue involved in a bipartite-charged hydrogen-bonding interaction with the backbone nitrogen-hydrogen atoms of asp2020. No DNA was available from the proband's deceased affected father and sister. The mutation was not found in more than 10,000 control genomes or exomes.

.0008 ADAMS-OLIVER SYNDROME 5

NOTCH1, TYR550TER

RCV000203698

In 5 affected members of a 3-generation family with Adams-Oliver syndrome-5 (AOS5; 616028), Southgate et al. (2015) identified heterozygosity for a 1-bp insertion (c.1649dupA, NM_017617.3) in the NOTCH1 gene, resulting in a tyr550-to-ter (Y550X) substitution within the EGF-like repeats of the extracellular domain. The proband and his brother each exhibited a severe cutaneous and bony scalp defect and marked terminal transverse limb defects, as well as an undefined heart murmur. The mutation was also present in their clinically unaffected mother, who had no scalp or limb defects but was found to have an unexplained heart murmur. Quantitative RT-PCR analysis of patient RNA demonstrated an approximately 50% reduction in NOTCH1 transcripts compared to control, and analysis of downstream signaling factors revealed significant reductions in HEY1 (602953) and HES1 (139605) with the Y550X mutant compared to wildtype NOTCH1.

.0009 ADAMS-OLIVER SYNDROME 5

NOTCH1, 2-BP DEL, 6049TC

RCV000206353...

In an Italian male proband with Adams-Oliver syndrome-5 (AOS5; 616028), originally reported by Dallapiccola et al. (1992), Southgate et al. (2015) identified heterozygosity for a 2-bp deletion (c.6049_6050delTC, NM_017617.3) in the NOTCH1 gene, causing a frameshift predicted to result in a premature termination codon (Ser2017ThrfsTer9) within the intracellular ANK repeat domain. DNA was unavailable from the proband's affected mother.

.0010 ADAMS-OLIVER SYNDROME 5

NOTCH1, CYS1374ARG

RCV000205222

In an 8-year-old German boy with Adams-Oliver syndrome-5 (AOS5; 616028), Southgate et al. (2015) identified heterozygosity for a c.4120T-C transition (c.4120T-C, NM_017617.3) in the NOTCH1 gene, resulting in a cys1374-to-arg (C1374R) substitution at a highly conserved residue within the EGF-like repeats of the extracellular domain. The mutation was present in an affected paternal uncle but was not found in 2 clinically normal sibs or 2 unaffected paternal uncles; however, it was a detected in the proband's clinically unaffected father. Cardiovascular evaluation by echocardiography showed no abnormality, confirming the father's unaffected status and indicating reduced penetrance for the C1374R mutation.

.0011 AORTIC VALVE DISEASE 1

NOTCH1, THR596MET

RCV000660144...

In a 49-year-old German man with a calcified bicuspid aortic valve and ascending aortic aneurysm (AOVD1; 109730), Mohamed et al. (2006) identified heterozygosity for a g.40264C-T transition in exon 11 of the NOTCH1 gene, resulting in a thr596-to-met (T596M) substitution at a highly conserved residue within an EGF-like domain in the N-terminal half of the protein. The authors stated in the text that the variant was not found in at least 327 controls or in public variant databases, but stated in table 3 that the variant had a minor allele frequency of 0.01.

.0012 AORTIC VALVE DISEASE 1

NOTCH1, PRO1797HIS

RCV000787044

In a 55-year-old German man with a calcified bicuspid aortic valve and ascending aortic aneurysm (AOVD1; 109730), Mohamed et al. (2006) identified heterozygosity for a g.53777A-C transversion in exon 29 of the NOTCH1 gene, resulting in a pro1797-to-his (P1797H) substitution at a highly conserved residue in the short juxtamembrane within the intracellular domain. The authors stated in the text that the variant was not found in at least 327 controls or in public variant databases, but stated in table 3 that the variant had a minor allele frequency of 0.01.

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Taniguchi, K., Wu, L.-W., Grivennikov, S. I., de Jong, P. R., Lian, I., Yu, F.-X., Wang, K., Ho, S. B., Boland, B. S., Chang, J. T., Sandborn, W. J., Hardiman, G., Raz, E., Maehara, Y., Yoshimura, A., Zucman-Rossi, J., Guan, K.-L., Karin, M. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519: 57-62, 2015. [PubMed: 25731159, images, related citations] [Full Text]
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Weaver, K. L., Alves-Guerra, M.-C., Jin, K., Wang, Z., Han, X., Ranganathan, P., Zhu, X., DaSilva, T., Liu, W., Ratti, F., Demarest, R. M., Tzimas, C., Rice, M., Vasquez-Del Carpio, R., Dahmane, N., Robbins, D. J., Capobianco, A. J. NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis. Cancer Res. 74: 4741-4751, 2014. [PubMed: 25038227, images, related citations] [Full Text]
Weijzen, S., Rizzo, P., Braid, M., Vaishnav, R., Jonkheer, S. M., Zlobin, A., Osborne, B. A., Gottipati, S., Aster, J. C., Hahn, W. C., Rudolf, M., Siziopikou, K., Kast, W. M., Miele, L. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nature Med. 8: 979-986, 2002. [PubMed: 12185362, related citations] [Full Text]
Weng, A. P., Ferrando, A. A., Lee, W., Morris, J. P., IV, Silverman, L. B., Sanchez-Irizarry, C., Blacklow, S. C., Look, A. T., Aster, J. C. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306: 269-271, 2004. [PubMed: 15472075, related citations] [Full Text]
Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., Wu, X., Ridgway, J., Schahin-Reed, D., Dow, G. J., and 12 others. Therapeutic antibody targeting of individual Notch receptors. Nature 464: 1052-1057, 2010. [PubMed: 20393564, related citations] [Full Text]
Yamamoto, S., Charng, W.-L., Rana, N. A., Kakuda, S., Jaiswal, M., Bayat, V., Xiong, B., Zhang, K., Sandoval, H., David, G., Wang, H., Haltiwanger, R. S., Bellen, H. J. A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands. Science 338: 1229-1232, 2012. [PubMed: 23197537, images, related citations] [Full Text]
Yang, G., Zhou, R., Zhou, Q., Guo, X., Yan, C., Ke, M., Lei, J., Shi, Y. Structural basis of Notch recognition by human gamma-secretase. Nature 565: 192-197, 2019. [PubMed: 30598546, related citations] [Full Text]
Ye, Y., Lukinova, N., Fortini, M. E. Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants. Nature 398: 525-529, 1999. [PubMed: 10206647, related citations] [Full Text]
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Yu, H., Saura, C. A., Choi, S.-Y., Sun, L. D., Yang, X., Handler, M., Kawarabayashi, T., Younkin, L., Fedeles, B., Wilson, M. A., Younkin, S., Kandel, E. R., Kirkwood, A., Shen, J. APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron 31: 713-726, 2001. [PubMed: 11567612, related citations] [Full Text]

Contributors:

Bao Lige - updated : 03/06/2025

Bao Lige - updated : 03/01/2022
Ada Hamosh - updated : 01/25/2021
Ada Hamosh - updated : 09/16/2020
Ada Hamosh - updated : 09/27/2019
Ada Hamosh - updated : 08/12/2019
Marla J. F. O'Neill - updated : 07/08/2019
Ada Hamosh - updated : 03/07/2019
Ada Hamosh - updated : 10/19/2018
Ada Hamosh - updated : 09/06/2018
Ada Hamosh - updated : 02/12/2018
Ada Hamosh - updated : 08/11/2017
Patricia A. Hartz - updated : 04/27/2017
Sarah M. Robbins - updated : 02/10/2017
Marla J. F. O'Neill - updated : 1/30/2016
Ada Hamosh - updated : 6/3/2015
Ada Hamosh - updated : 3/11/2015
Ada Hamosh - updated : 11/10/2014
Marla J. F. O'Neill - updated : 9/24/2014
Paul J. Converse - updated : 7/2/2014
Ada Hamosh - updated : 1/31/2014
Ada Hamosh - updated : 1/15/2014
Ada Hamosh - updated : 1/14/2013
Paul J. Converse - updated : 7/16/2012
Patricia A. Hartz - updated : 6/8/2012
Marla J. F. O'Neill - updated : 2/14/2012
Cassandra L. Kniffin - updated : 1/25/2012
Ada Hamosh - updated : 9/21/2011
Ada Hamosh - updated : 6/22/2011
Ada Hamosh - updated : 5/23/2011
Ada Hamosh - updated : 9/29/2010
Ada Hamosh - updated : 6/8/2010
Ada Hamosh - updated : 5/27/2010
Ada Hamosh - updated : 2/18/2010
Patricia A. Hartz - updated : 1/20/2010
Ada Hamosh - updated : 12/29/2009
George E. Tiller - updated : 10/15/2009
Cassandra L. Kniffin - updated : 2/12/2009
Ada Hamosh - updated : 8/13/2008
Patricia A. Hartz - updated : 5/29/2008
Patricia A. Hartz - updated : 3/13/2008
Ada Hamosh - updated : 1/10/2008
Cassandra L. Kniffin - updated : 10/25/2007
Patricia A. Hartz - updated : 9/21/2007
Patricia A. Hartz - updated : 7/10/2007
Ada Hamosh - updated : 7/5/2007
Ada Hamosh - updated : 6/26/2007
Paul J. Converse - updated : 6/7/2007
Patricia A. Hartz - updated : 5/7/2007
Marla J. F. O'Neill - updated : 2/26/2007
Patricia A. Hartz - updated : 1/26/2007
Ada Hamosh - updated : 1/23/2007
Paul J. Converse - updated : 12/20/2006
Paul J. Converse - updated : 6/20/2006
Patricia A. Hartz - updated : 1/26/2006
Marla J. F. O'Neill - updated : 12/16/2005
Patricia A. Hartz - updated : 12/13/2005
Paul J. Converse - updated : 10/20/2005
Matthew B. Gross - reorganized : 10/3/2005
Joanna S. Amberger - updated : 10/3/2005
Patricia A. Hartz - updated : 9/20/2005
Ada Hamosh - updated : 9/7/2005
Patricia A. Hartz - updated : 6/30/2005
Ada Hamosh - updated : 6/3/2005
Ada Hamosh - updated : 2/2/2005
Ada Hamosh - updated : 6/8/2004
Patricia A. Hartz - updated : 5/12/2004
Ada Hamosh - updated : 1/22/2004
Ada Hamosh - updated : 12/3/2003
Cassandra L. Kniffin - updated : 5/16/2003
Ada Hamosh - updated : 5/6/2003
Deborah L. Stone - updated : 3/26/2003
Dawn Watkins-Chow - updated : 2/27/2003
Victor A. McKusick - updated : 2/20/2003
Stylianos E. Antonarakis - updated : 1/17/2003
Ada Hamosh - updated : 1/17/2003
Ada Hamosh - updated : 9/30/2002
Dawn Watkins-Chow - updated : 2/14/2002
Paul J. Converse - updated : 11/26/2001
Victor A. McKusick - updated : 7/6/2001
Ada Hamosh - updated : 4/26/2001
Ada Hamosh - updated : 11/30/2000
Ada Hamosh - updated : 8/2/2000
Ada Hamosh - updated : 7/27/2000
Patti M. Sherman - updated : 7/13/2000
Ada Hamosh - updated : 6/20/2000
Stylianos E. Antonarakis - updated : 3/27/2000
Ada Hamosh - updated : 10/20/1999
Victor A. McKusick - updated : 4/6/1999
Moyra Smith - updated : 3/28/1996

Creation Date:

Victor A. McKusick : 10/28/1991

Edit History:

mgross : 03/06/2025

alopez : 08/04/2022
carol : 03/02/2022
mgross : 03/01/2022
mgross : 02/09/2021
mgross : 01/25/2021
alopez : 09/16/2020
carol : 02/05/2020
alopez : 09/27/2019
alopez : 08/12/2019
alopez : 08/12/2019
carol : 08/07/2019
carol : 07/24/2019
carol : 07/08/2019
alopez : 03/07/2019
alopez : 12/21/2018
carol : 11/26/2018
alopez : 10/19/2018
alopez : 09/06/2018
carol : 02/13/2018
alopez : 02/12/2018
carol : 10/05/2017
alopez : 08/11/2017
carol : 04/27/2017
carol : 04/19/2017
mgross : 02/10/2017
alopez : 12/19/2016
carol : 09/06/2016
carol : 03/16/2016
carol : 1/30/2016
alopez : 6/3/2015
alopez : 3/11/2015
alopez : 11/10/2014
carol : 9/29/2014
carol : 9/25/2014
mcolton : 9/24/2014
mgross : 7/2/2014
mcolton : 7/2/2014
alopez : 1/31/2014
alopez : 1/15/2014
mgross : 10/7/2013
alopez : 1/16/2013
terry : 1/14/2013
terry : 12/20/2012
terry : 12/19/2012
carol : 9/17/2012
carol : 9/17/2012
mgross : 7/20/2012
terry : 7/16/2012
mgross : 6/8/2012
terry : 6/7/2012
alopez : 4/25/2012
alopez : 4/11/2012
alopez : 3/7/2012
carol : 2/15/2012
terry : 2/14/2012
carol : 2/1/2012
ckniffin : 1/25/2012
alopez : 9/23/2011
alopez : 9/23/2011
alopez : 9/23/2011
alopez : 9/23/2011
terry : 9/21/2011
alopez : 6/27/2011
terry : 6/22/2011
alopez : 5/24/2011
terry : 5/23/2011
alopez : 10/4/2010
terry : 9/29/2010
terry : 9/9/2010
alopez : 6/8/2010
terry : 6/8/2010
alopez : 6/1/2010
terry : 5/27/2010
terry : 5/27/2010
terry : 2/18/2010
mgross : 1/20/2010
alopez : 1/5/2010
terry : 12/29/2009
wwang : 10/20/2009
terry : 10/15/2009
wwang : 3/4/2009
ckniffin : 2/12/2009
alopez : 8/20/2008
terry : 8/13/2008
mgross : 6/3/2008
terry : 5/29/2008
mgross : 3/18/2008
terry : 3/13/2008
ckniffin : 2/5/2008
alopez : 1/28/2008
terry : 1/10/2008
wwang : 11/5/2007
ckniffin : 10/25/2007
mgross : 9/27/2007
terry : 9/21/2007
terry : 7/10/2007
alopez : 7/5/2007
alopez : 7/2/2007
terry : 6/26/2007
mgross : 6/7/2007
mgross : 6/7/2007
wwang : 5/7/2007
wwang : 2/26/2007
mgross : 1/26/2007
mgross : 1/26/2007
alopez : 1/25/2007
terry : 1/23/2007
mgross : 12/20/2006
carol : 8/16/2006
alopez : 8/3/2006
terry : 8/1/2006
mgross : 6/20/2006
mgross : 2/2/2006
terry : 1/26/2006
wwang : 12/16/2005
wwang : 12/13/2005
mgross : 10/20/2005
mgross : 10/20/2005
mgross : 10/4/2005
mgross : 10/3/2005
mgross : 10/3/2005
mgross : 10/3/2005
joanna : 10/3/2005
wwang : 9/21/2005
wwang : 9/20/2005
alopez : 9/14/2005
alopez : 9/14/2005
terry : 9/7/2005
wwang : 6/30/2005
wwang : 6/7/2005
wwang : 6/3/2005
alopez : 2/23/2005
terry : 2/2/2005
terry : 7/1/2004
alopez : 6/9/2004
terry : 6/8/2004
mgross : 5/13/2004
terry : 5/12/2004
alopez : 1/22/2004
terry : 1/22/2004
alopez : 12/8/2003
terry : 12/3/2003
alopez : 5/28/2003
cwells : 5/22/2003
ckniffin : 5/16/2003
alopez : 5/6/2003
alopez : 5/6/2003
terry : 5/6/2003
carol : 3/26/2003
carol : 3/26/2003
carol : 3/26/2003
tkritzer : 3/24/2003
tkritzer : 3/24/2003
alopez : 3/12/2003
carol : 3/4/2003
tkritzer : 2/27/2003
tkritzer : 2/27/2003
alopez : 2/21/2003
terry : 2/20/2003
mgross : 1/17/2003
alopez : 1/17/2003
terry : 1/17/2003
terry : 1/17/2003
alopez : 10/1/2002
tkritzer : 9/30/2002
carol : 3/1/2002
terry : 2/14/2002
mgross : 12/5/2001
terry : 11/26/2001
alopez : 7/16/2001
mcapotos : 7/6/2001
mcapotos : 5/7/2001
mcapotos : 5/3/2001
terry : 4/26/2001
mcapotos : 2/13/2001
carol : 12/1/2000
terry : 11/30/2000
terry : 10/6/2000
mgross : 9/15/2000
mcapotos : 8/7/2000
alopez : 8/2/2000
alopez : 7/27/2000
alopez : 7/27/2000
mcapotos : 7/21/2000
psherman : 7/13/2000
alopez : 6/21/2000
carol : 6/20/2000
mgross : 3/27/2000
alopez : 10/23/1999
terry : 10/20/1999
alopez : 4/7/1999
carol : 4/6/1999
mark : 1/19/1998
mark : 8/5/1996
mark : 4/25/1996
mark : 3/28/1996
mark : 3/28/1996
mark : 2/7/1996
mimadm : 6/7/1995
carol : 1/5/1995
davew : 6/9/1994
jason : 6/7/1994
carol : 7/1/1993
supermim : 3/16/1992

* 190198

NOTCH RECEPTOR 1; NOTCH1

Alternative titles; symbols

NOTCH, DROSOPHILA, HOMOLOG OF, 1
TRANSLOCATION-ASSOCIATED NOTCH HOMOLOG; TAN1

HGNC Approved Gene Symbol: NOTCH1

Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38) : 9:136,494,433-136,546,048 (from NCBI)

Gene-Phenotype Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
9q34.3	Adams-Oliver syndrome 5	616028	Autosomal dominant	3
9q34.3	Aortic valve disease 1	109730	Autosomal dominant	3

TEXT

Description

Cloning and Expression

Biochemical Features

Crystal Structure

Cryoelectron Microscopy

Mapping

Del Amo et al. (1993) and Pilz et al. (1994) demonstrated that the mouse Notch1 gene maps to chromosome 2.

Gene Function

Notch Ligand Selectivity

Processing of Notch

Role of Presenilins in Notch Processing

Modulation of Notch Signaling by Fringe Proteins

Modulation of Notch Signaling by POFUT1

Modulation of Notch Signaling by PIN1

Modulation of Notch Signaling by USP10

Notch Signaling Pathway

Artavanis-Tsakonas et al. (1995) reviewed the Notch signaling pathway.

Role of Notch in Early Embryonic Development

Role of Notch in Cell Fate Determination

Role of Notch in Neural Development

Role of Notch in Muscle Regeneration

Role of Notch in Bone Homeostasis

Cytogenetics

Molecular Genetics

Aortic Valve Disease

Other Cardiac Malformations

Adams-Oliver Syndrome 5

T-cell Acute Lymphoblastic Leukemia

Isolated Juvenile or Chronic Myelomonocytic Leukemia

Chronic Lymphocytic Leukemia

Quesada et al. (2012) identified somatic mutations in the NOTCH1 gene in 25 (9.5%) of 260 cases of CLL.

Head and Neck Squamous Cell Carcinoma

Mutation in Normal Esophageal Epithelium

Animal Model

ALLELIC VARIANTS 12 Selected Examples):

.0001 AORTIC VALVE DISEASE 1

NOTCH1, ARG1108TER
SNP: rs41309764, gnomAD: rs41309764, ClinVar: RCV000013294, RCV001781254, RCV001851821

.0002 AORTIC VALVE DISEASE 1

NOTCH1, 1-BP DEL, NT4515
SNP: rs41309766, gnomAD: rs41309766, ClinVar: RCV000013295

.0003 ADAMS-OLIVER SYNDROME 5

NOTCH1, 85-KB DEL
ClinVar: RCV000144232

.0004 ADAMS-OLIVER SYNDROME 5

NOTCH1, IVS4AS, G-T, -1
SNP: rs587777735, ClinVar: RCV000144234

.0005 ADAMS-OLIVER SYNDROME 5

NOTCH1, CYS429ARG
SNP: rs587777736, ClinVar: RCV000144235

.0006 ADAMS-OLIVER SYNDROME 5

NOTCH1, CYS1496TYR
SNP: rs587781259, ClinVar: RCV000144236

.0007 ADAMS-OLIVER SYNDROME 5

NOTCH1, ASP1989ASN
SNP: rs587777734, ClinVar: RCV000144233

.0008 ADAMS-OLIVER SYNDROME 5

NOTCH1, TYR550TER
SNP: rs864622059, ClinVar: RCV000203698

.0009 ADAMS-OLIVER SYNDROME 5

NOTCH1, 2-BP DEL, 6049TC
SNP: rs864622063, ClinVar: RCV000206353, RCV004767148

.0010 ADAMS-OLIVER SYNDROME 5

NOTCH1, CYS1374ARG
SNP: rs864622060, ClinVar: RCV000205222

.0011 AORTIC VALVE DISEASE 1

NOTCH1, THR596MET
SNP: rs61755997, gnomAD: rs61755997, ClinVar: RCV000660144, RCV000787043, RCV001049180, RCV001575577, RCV002311202, RCV004701355

.0012 AORTIC VALVE DISEASE 1

NOTCH1, PRO1797HIS
ClinVar: RCV000787044

REFERENCES

Agrawal, N., Frederick, M. J., Pickering, C. R., Bettegowda, C., Chang, K., Li, R. J., Fakhry, C., Xie, T.-X., Zhang, J., Wang, J., Zhang, N., El-Naggar, A. K., and 19 others. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333: 1154-1157, 2011. [PubMed: 21798897] [Full Text: https://doi.org/10.1126/science.1206923]
Aguirre, A., Rubio, M. E., Gallo, V. Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature 467: 323-327, 2010. [PubMed: 20844536] [Full Text: https://doi.org/10.1038/nature09347]
Artavanis-Tsakonas, S., Matsuno, K., Fortini, M. Notch signaling. Science 268: 225-232, 1995. [PubMed: 7716513] [Full Text: https://doi.org/10.1126/science.7716513]
Axelrod, J. D., Matsuno, K., Artavanis-Tsakonas, S., Perrimon, N. Interaction between Wingless and Notch signaling pathways mediated by Dishevelled. Science 271: 1826-1832, 1996. [PubMed: 8596950] [Full Text: https://doi.org/10.1126/science.271.5257.1826]
Balint, K., Xiao, M., Pinnix, C. C., Soma, A., Veres, I., Juhasz, I., Brown, E. J., Capobianco, A. J., Herlyn, M., Liu, Z.-J. Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression. J. Clin. Invest. 115: 3166-3176, 2005. [PubMed: 16239965] [Full Text: https://doi.org/10.1172/JCI25001]
Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484: 110-114, 2012. [PubMed: 22426001] [Full Text: https://doi.org/10.1038/nature10908]
Boskovski, M. T., Yuan, S., Pedersen, N. B., Goth, C. K., Makova, S., Clausen, H., Brueckner, M., Khokha, M. K. The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality. Nature 504: 456-459, 2013. [PubMed: 24226769] [Full Text: https://doi.org/10.1038/nature12723]
Brou, C., Logeat, F., Gupta, N., Bessia, C., LeBail, O., Doedens, J. R., Cumano, A., Roux, P., Black, R. A., Israel, A. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Molec. Cell 5: 207-216, 2000. [PubMed: 10882063] [Full Text: https://doi.org/10.1016/s1097-2765(00)80417-7]
Bruckner, K., Perez, L., Clausen, H., Cohen, S. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406: 411-415, 2000. Note: Erratum: Nature 407: 654 only, 2000. [PubMed: 10935637] [Full Text: https://doi.org/10.1038/35019075]
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Contributors:

Bao Lige - updated : 03/06/2025
Bao Lige - updated : 03/01/2022
Ada Hamosh - updated : 01/25/2021
Ada Hamosh - updated : 09/16/2020
Ada Hamosh - updated : 09/27/2019
Ada Hamosh - updated : 08/12/2019
Marla J. F. O'Neill - updated : 07/08/2019
Ada Hamosh - updated : 03/07/2019
Ada Hamosh - updated : 10/19/2018
Ada Hamosh - updated : 09/06/2018
Ada Hamosh - updated : 02/12/2018
Ada Hamosh - updated : 08/11/2017
Patricia A. Hartz - updated : 04/27/2017
Sarah M. Robbins - updated : 02/10/2017
Marla J. F. O'Neill - updated : 1/30/2016
Ada Hamosh - updated : 6/3/2015
Ada Hamosh - updated : 3/11/2015
Ada Hamosh - updated : 11/10/2014
Marla J. F. O'Neill - updated : 9/24/2014
Paul J. Converse - updated : 7/2/2014
Ada Hamosh - updated : 1/31/2014
Ada Hamosh - updated : 1/15/2014
Ada Hamosh - updated : 1/14/2013
Paul J. Converse - updated : 7/16/2012
Patricia A. Hartz - updated : 6/8/2012
Marla J. F. O'Neill - updated : 2/14/2012
Cassandra L. Kniffin - updated : 1/25/2012
Ada Hamosh - updated : 9/21/2011
Ada Hamosh - updated : 6/22/2011
Ada Hamosh - updated : 5/23/2011
Ada Hamosh - updated : 9/29/2010
Ada Hamosh - updated : 6/8/2010
Ada Hamosh - updated : 5/27/2010
Ada Hamosh - updated : 2/18/2010
Patricia A. Hartz - updated : 1/20/2010
Ada Hamosh - updated : 12/29/2009
George E. Tiller - updated : 10/15/2009
Cassandra L. Kniffin - updated : 2/12/2009
Ada Hamosh - updated : 8/13/2008
Patricia A. Hartz - updated : 5/29/2008
Patricia A. Hartz - updated : 3/13/2008
Ada Hamosh - updated : 1/10/2008
Cassandra L. Kniffin - updated : 10/25/2007
Patricia A. Hartz - updated : 9/21/2007
Patricia A. Hartz - updated : 7/10/2007
Ada Hamosh - updated : 7/5/2007
Ada Hamosh - updated : 6/26/2007
Paul J. Converse - updated : 6/7/2007
Patricia A. Hartz - updated : 5/7/2007
Marla J. F. O'Neill - updated : 2/26/2007
Patricia A. Hartz - updated : 1/26/2007
Ada Hamosh - updated : 1/23/2007
Paul J. Converse - updated : 12/20/2006
Paul J. Converse - updated : 6/20/2006
Patricia A. Hartz - updated : 1/26/2006
Marla J. F. O'Neill - updated : 12/16/2005
Patricia A. Hartz - updated : 12/13/2005
Paul J. Converse - updated : 10/20/2005
Matthew B. Gross - reorganized : 10/3/2005
Joanna S. Amberger - updated : 10/3/2005
Patricia A. Hartz - updated : 9/20/2005
Ada Hamosh - updated : 9/7/2005
Patricia A. Hartz - updated : 6/30/2005
Ada Hamosh - updated : 6/3/2005
Ada Hamosh - updated : 2/2/2005
Ada Hamosh - updated : 6/8/2004
Patricia A. Hartz - updated : 5/12/2004
Ada Hamosh - updated : 1/22/2004
Ada Hamosh - updated : 12/3/2003
Cassandra L. Kniffin - updated : 5/16/2003
Ada Hamosh - updated : 5/6/2003
Deborah L. Stone - updated : 3/26/2003
Dawn Watkins-Chow - updated : 2/27/2003
Victor A. McKusick - updated : 2/20/2003
Stylianos E. Antonarakis - updated : 1/17/2003
Ada Hamosh - updated : 1/17/2003
Ada Hamosh - updated : 9/30/2002
Dawn Watkins-Chow - updated : 2/14/2002
Paul J. Converse - updated : 11/26/2001
Victor A. McKusick - updated : 7/6/2001
Ada Hamosh - updated : 4/26/2001
Ada Hamosh - updated : 11/30/2000
Ada Hamosh - updated : 8/2/2000
Ada Hamosh - updated : 7/27/2000
Patti M. Sherman - updated : 7/13/2000
Ada Hamosh - updated : 6/20/2000
Stylianos E. Antonarakis - updated : 3/27/2000
Ada Hamosh - updated : 10/20/1999
Victor A. McKusick - updated : 4/6/1999
Moyra Smith - updated : 3/28/1996

Creation Date:

Victor A. McKusick : 10/28/1991

Edit History:

mgross : 03/06/2025
alopez : 08/04/2022
carol : 03/02/2022
mgross : 03/01/2022
mgross : 02/09/2021
mgross : 01/25/2021
alopez : 09/16/2020
carol : 02/05/2020
alopez : 09/27/2019
alopez : 08/12/2019
alopez : 08/12/2019
carol : 08/07/2019
carol : 07/24/2019
carol : 07/08/2019
alopez : 03/07/2019
alopez : 12/21/2018
carol : 11/26/2018
alopez : 10/19/2018
alopez : 09/06/2018
carol : 02/13/2018
alopez : 02/12/2018
carol : 10/05/2017
alopez : 08/11/2017
carol : 04/27/2017
carol : 04/19/2017
mgross : 02/10/2017
alopez : 12/19/2016
carol : 09/06/2016
carol : 03/16/2016
carol : 1/30/2016
alopez : 6/3/2015
alopez : 3/11/2015
alopez : 11/10/2014
carol : 9/29/2014
carol : 9/25/2014
mcolton : 9/24/2014
mgross : 7/2/2014
mcolton : 7/2/2014
alopez : 1/31/2014
alopez : 1/15/2014
mgross : 10/7/2013
alopez : 1/16/2013
terry : 1/14/2013
terry : 12/20/2012
terry : 12/19/2012
carol : 9/17/2012
carol : 9/17/2012
mgross : 7/20/2012
terry : 7/16/2012
mgross : 6/8/2012
terry : 6/7/2012
alopez : 4/25/2012
alopez : 4/11/2012
alopez : 3/7/2012
carol : 2/15/2012
terry : 2/14/2012
carol : 2/1/2012
ckniffin : 1/25/2012
alopez : 9/23/2011
alopez : 9/23/2011
alopez : 9/23/2011
alopez : 9/23/2011
terry : 9/21/2011
alopez : 6/27/2011
terry : 6/22/2011
alopez : 5/24/2011
terry : 5/23/2011
alopez : 10/4/2010
terry : 9/29/2010
terry : 9/9/2010
alopez : 6/8/2010
terry : 6/8/2010
alopez : 6/1/2010
terry : 5/27/2010
terry : 5/27/2010
terry : 2/18/2010
mgross : 1/20/2010
alopez : 1/5/2010
terry : 12/29/2009
wwang : 10/20/2009
terry : 10/15/2009
wwang : 3/4/2009
ckniffin : 2/12/2009
alopez : 8/20/2008
terry : 8/13/2008
mgross : 6/3/2008
terry : 5/29/2008
mgross : 3/18/2008
terry : 3/13/2008
ckniffin : 2/5/2008
alopez : 1/28/2008
terry : 1/10/2008
wwang : 11/5/2007
ckniffin : 10/25/2007
mgross : 9/27/2007
terry : 9/21/2007
terry : 7/10/2007
alopez : 7/5/2007
alopez : 7/2/2007
terry : 6/26/2007
mgross : 6/7/2007
mgross : 6/7/2007
wwang : 5/7/2007
wwang : 2/26/2007
mgross : 1/26/2007
mgross : 1/26/2007
alopez : 1/25/2007
terry : 1/23/2007
mgross : 12/20/2006
carol : 8/16/2006
alopez : 8/3/2006
terry : 8/1/2006
mgross : 6/20/2006
mgross : 2/2/2006
terry : 1/26/2006
wwang : 12/16/2005
wwang : 12/13/2005
mgross : 10/20/2005
mgross : 10/20/2005
mgross : 10/4/2005
mgross : 10/3/2005
mgross : 10/3/2005
mgross : 10/3/2005
joanna : 10/3/2005
wwang : 9/21/2005
wwang : 9/20/2005
alopez : 9/14/2005
alopez : 9/14/2005
terry : 9/7/2005
wwang : 6/30/2005
wwang : 6/7/2005
wwang : 6/3/2005
alopez : 2/23/2005
terry : 2/2/2005
terry : 7/1/2004
alopez : 6/9/2004
terry : 6/8/2004
mgross : 5/13/2004
terry : 5/12/2004
alopez : 1/22/2004
terry : 1/22/2004
alopez : 12/8/2003
terry : 12/3/2003
alopez : 5/28/2003
cwells : 5/22/2003
ckniffin : 5/16/2003
alopez : 5/6/2003
alopez : 5/6/2003
terry : 5/6/2003
carol : 3/26/2003
carol : 3/26/2003
carol : 3/26/2003
tkritzer : 3/24/2003
tkritzer : 3/24/2003
alopez : 3/12/2003
carol : 3/4/2003
tkritzer : 2/27/2003
tkritzer : 2/27/2003
alopez : 2/21/2003
terry : 2/20/2003
mgross : 1/17/2003
alopez : 1/17/2003
terry : 1/17/2003
terry : 1/17/2003
alopez : 10/1/2002
tkritzer : 9/30/2002
carol : 3/1/2002
terry : 2/14/2002
mgross : 12/5/2001
terry : 11/26/2001
alopez : 7/16/2001
mcapotos : 7/6/2001
mcapotos : 5/7/2001
mcapotos : 5/3/2001
terry : 4/26/2001
mcapotos : 2/13/2001
carol : 12/1/2000
terry : 11/30/2000
terry : 10/6/2000
mgross : 9/15/2000
mcapotos : 8/7/2000
alopez : 8/2/2000
alopez : 7/27/2000
alopez : 7/27/2000
mcapotos : 7/21/2000
psherman : 7/13/2000
alopez : 6/21/2000
carol : 6/20/2000
mgross : 3/27/2000
alopez : 10/23/1999
terry : 10/20/1999
alopez : 4/7/1999
carol : 4/6/1999
mark : 1/19/1998
mark : 8/5/1996
mark : 4/25/1996
mark : 3/28/1996
mark : 3/28/1996
mark : 2/7/1996
mimadm : 6/7/1995
carol : 1/5/1995
davew : 6/9/1994
jason : 6/7/1994
carol : 7/1/1993
supermim : 3/16/1992

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM^® and Online Mendelian Inheritance in Man^® are registered trademarks of the Johns Hopkins University.
Copyright^® 1966-2025 Johns Hopkins University.
Printed: March 13, 2025

▼ External Links

NOTCH RECEPTOR 1; NOTCH1

NOTCH, DROSOPHILA, HOMOLOG OF, 1 TRANSLOCATION-ASSOCIATED NOTCH HOMOLOG; TAN1

TEXT

▼ Description

▼ Cloning and Expression

▼ Biochemical Features

▼ Mapping

▼ Gene Function

▼ Cytogenetics

▼ Molecular Genetics

▼ Animal Model

▼ ALLELIC VARIANTS ( 12 Selected Examples):

.0001 AORTIC VALVE DISEASE 1

.0002 AORTIC VALVE DISEASE 1

.0003 ADAMS-OLIVER SYNDROME 5

.0004 ADAMS-OLIVER SYNDROME 5

.0005 ADAMS-OLIVER SYNDROME 5

.0006 ADAMS-OLIVER SYNDROME 5

.0007 ADAMS-OLIVER SYNDROME 5

.0008 ADAMS-OLIVER SYNDROME 5

.0009 ADAMS-OLIVER SYNDROME 5

.0010 ADAMS-OLIVER SYNDROME 5

.0011 AORTIC VALVE DISEASE 1

.0012 AORTIC VALVE DISEASE 1

▼ REFERENCES

* 190198

NOTCH RECEPTOR 1; NOTCH1

NOTCH, DROSOPHILA, HOMOLOG OF, 1 TRANSLOCATION-ASSOCIATED NOTCH HOMOLOG; TAN1

Gene-Phenotype Relationships

TEXT

Description

Cloning and Expression

Biochemical Features

Mapping

Gene Function

Cytogenetics

Molecular Genetics

Animal Model

ALLELIC VARIANTS 12 Selected Examples):

.0001 AORTIC VALVE DISEASE 1

.0002 AORTIC VALVE DISEASE 1

.0003 ADAMS-OLIVER SYNDROME 5

.0004 ADAMS-OLIVER SYNDROME 5

.0005 ADAMS-OLIVER SYNDROME 5

.0006 ADAMS-OLIVER SYNDROME 5

.0007 ADAMS-OLIVER SYNDROME 5

.0008 ADAMS-OLIVER SYNDROME 5

.0009 ADAMS-OLIVER SYNDROME 5

.0010 ADAMS-OLIVER SYNDROME 5

.0011 AORTIC VALVE DISEASE 1

.0012 AORTIC VALVE DISEASE 1

REFERENCES

▼

External Links

NOTCH, DROSOPHILA, HOMOLOG OF, 1
TRANSLOCATION-ASSOCIATED NOTCH HOMOLOG; TAN1

NOTCH, DROSOPHILA, HOMOLOG OF, 1
TRANSLOCATION-ASSOCIATED NOTCH HOMOLOG; TAN1