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Gene Review

Notch1  -  notch 1

Mus musculus

Synonyms: 9930111A19Rik, Mis6, Motch, Motch A, N1, ...
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Disease relevance of Notch1

  • Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis [1].
  • Itch genetically interacts with Notch1 in a mouse autoimmune disease model [2].
  • In the coculture on the monolayer of OP-9, which was originally known to support B cell specific development, hemopoietic progenitors developed into Thy-1(+)CD25(+) T lineage cells if the progenitor cells were infected with the retrovirus containing Notch1 intracellular domains [3].
  • RESULTS: We observed that N2a neuroblastoma cells expressing an activated form of Notch, Notch1(IC), produced shorter neurites compared with controls, whereas N2a cell lines expressing a dominant-negative Notch1 or a dominant-negative Delta1 construct extended longer neurites with a greater number of primary neurites [4].
  • In the present work we present evidence that gamma-radiation-induced thymic lymphomas in (C57BL/6 J x BALB/c) F1 hybrid mice often exhibit increased levels of Notch1 expression, but, contrary to what was expected, they also exhibit a clearly reduced Notch2 mRNA expression, suggesting a cooperative antagonism of these genes [5].
  • These results provide a molecular and cellular framework for understanding the role of Notch signaling in the etiology of congenital heart disease [6].
  • Notch1 co-opts Lef1 during the process of transformation to maintain survival of T-cell lymphomas [7].

Psychiatry related information on Notch1


High impact information on Notch1

  • HectH9-mediated ubiquitination of Myc is required for transactivation of multiple target genes, recruitment of the coactivator p300, and induction of cell proliferation by Myc [12].
  • Expression of the basic helix-loop-helix factor Hes7, an effector of Notch signaling, follows a 2-hour oscillatory cycle controlled by negative feedback; this is proposed to be the molecular basis for the somite segmentation clock [13].
  • Th2 differentiation induced by APC is abrogated in T cells lacking the Notch effector RBPJkappa [14].
  • Expression of these different Notch ligands on APC is induced by Th1- or Th2-promoting stimuli [14].
  • Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors [1].

Chemical compound and disease context of Notch1

  • Additionally, the aberrant expression of adipsin, and its presence in feces may serve as a noninvasive biomarker of gastrointestinal toxicity associated with perturbed Notch signaling [15].
  • The efficacy of STI571 in reducing Abeta without affecting Notch-1 cleavage may prove useful as a basis for developing novel therapies for Alzheimer's disease [16].
  • Interestingly, the signals generated by pertussis toxin, which increase Notch expression, can dominate the signals by phorbol ester and ionomycin, steering thymocyte development to CD8 lineage [17].

Biological context of Notch1

  • Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin [1].
  • Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos [18].
  • Here, we show that suppression of Wnt signaling by Notch1 activation is mediated, at least in part, by down-modulation of Wnts gene expression. p21 is a negative regulator of Wnts transcription downstream of Notch1 activation, independently of effects on the cell cycle [19].
  • The Notch1 tumor-suppressor function was associated with down-regulation of Wnt signaling [19].
  • Consistent with these results, expression of Cre recombinase in sensory neurons from numb conditional mutants results in reduced endocytosis, a significant increase in nuclear Notch1, and severe reductions in axon branch points and total axon length [20].

Anatomical context of Notch1

  • Here we show that genes encoding the receptor protein Notch1 and its ligand, Jagged 2, are expressed in alternating cell types in the developing sensory epithelium [21].
  • Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice [1].
  • Hence, PS1 is required for the spatiotemporal expression of Notch1 and Dll1, which are essential for somite segmentation and maintenance of somite borders [22].
  • Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm [22].
  • Pax5 thereby interfered with T lineage commitment and early thymocyte development by repressing the transcription of the T cell specification gene Notch1 [23].

Associations of Notch1 with chemical compounds

  • However, T cell induction by intracellular Notch1 failed unless both OP-9 and IL-7 were present [3].
  • Cortisol increased the rate of Notch1 and 2 transcription and, in transcriptionally arrested cells, did not modify the decay of the transcripts, indicating a transcriptional level of control [24].
  • The elevated expression of Notch1 and Notch2 induced by lipopolysaccharide was repressed by testosterone at lower levels, but enhanced at higher hormone levels [25].
  • Unique patterns of Notch1, Notch4 and Jagged1 expression in ovarian vessels during folliculogenesis and corpus luteum formation [26].
  • Finally we found that OPC-targeted Notch1 ablation in cuprizone-treated Plp-creER Notch1(lox/lox) transgenic mice yielded no significant differences in remyelination parameters between knock-out and control mice [27].
  • Accordingly, we found that Notch1 signaling is linked to vitamin A metabolism by regulating the expression of cellular retinol binding protein 1 (CRBP1), required to generate a pool of intracellular retinol [28].
  • Overall, our data suggest that an important relationship exists between LPS-mediated inflammation and the Notch1 signaling pathway, and that this relationship intimately involves the nitration of Notch1-IC tyrosine residues [29].

Physical interactions of Notch1

  • Functional involvement of the Notch pathway in osteoblastic differentiation has been previously investigated using the truncated intracellular domain, which mimics Notch signaling by interacting with the DNA-binding protein CBF-1 [30].
  • Mfge8 (milk fat globule-EGF-factor 8) encodes a soluble integrin-binding protein containing two Notch-like EGF domains and two discoidin domains [31].
  • We show here that both mouse and human promoter regions of Nrarp share two conserved regions located approximately 2 and approximately 3 kb upstream of the transcription start site each containing a perfect putative binding site for the Notch-dependent transcription factor Su(H) [32].
  • For instance, in fetal brain, it has been shown that the neurogenic transcription factor Neurogenin1 inhibits formation of a STAT3/p300/ Smad1 complex and that the oligodendrocytic transcription factor OLIG2 does the same [33].
  • Here we demonstrate that, in differentiating skeletal muscle cells, p300 physically interacts with the myogenic basic helix-loop-helix (bHLH) regulatory protein MyoD at its DNA binding sites [34].

Enzymatic interactions of Notch1

  • We show that full-length Notch1 [N1(FL)] transfected into wild type (WT) primary neurons is cleaved in the presence of its biological ligand Delta (Dl) and translocated to the nucleus within 1--3 min of ligand addition [35].
  • Presenilin-1 D257A and D385A mutants fail to cleave Notch in their endoproteolyzed forms, but only presenilin-1 D385A mutant can restore its gamma-secretase activity with the compensatory overexpression of normal C-terminal fragment [36].

Regulatory relationships of Notch1


Other interactions of Notch1

  • Examination of the RNA expression pattern of the Notch2 gene, another Notch gene family member, indicated that it partially overlapped the Notch1 expression pattern [43].
  • Mouse Numb homologs antagonize Notch1 signaling pathways through largely unknown mechanisms [20].
  • However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene [18].
  • Thus, p21 acts as a selective negative regulator of transcription and links the Notch and Wnt signaling pathways in keratinocyte growth control [19].
  • The Notch target genes Hey1 and Hey2 are required for embryonic vascular development [44].
  • Inhibition of Notch signaling at this stage appears to be mediated by the transient expression of Numb in the hemangioblast-derived blast cell colonies [45].

Analytical, diagnostic and therapeutic context of Notch1


  1. Notch1 functions as a tumor suppressor in mouse skin. Nicolas, M., Wolfer, A., Raj, K., Kummer, J.A., Mill, P., van Noort, M., Hui, C.C., Clevers, H., Dotto, G.P., Radtke, F. Nat. Genet. (2003) [Pubmed]
  2. Itch genetically interacts with Notch1 in a mouse autoimmune disease model. Matesic, L.E., Haines, D.C., Copeland, N.G., Jenkins, N.A. Hum. Mol. Genet. (2006) [Pubmed]
  3. Active form of Notch members can enforce T lymphopoiesis on lymphoid progenitors in the monolayer culture specific for B cell development. Hozumi, K., Abe, N., Chiba, S., Hirai, H., Habu, S. J. Immunol. (2003) [Pubmed]
  4. Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1. Franklin, J.L., Berechid, B.E., Cutting, F.B., Presente, A., Chambers, C.B., Foltz, D.R., Ferreira, A., Nye, J.S. Curr. Biol. (1999) [Pubmed]
  5. Defective expression of Notch1 and Notch2 in connection to alterations of c-Myc and Ikaros in gamma-radiation-induced mouse thymic lymphomas. López-Nieva, P., Santos, J., Fernández-Piqueras, J. Carcinogenesis (2004) [Pubmed]
  6. An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. High, F.A., Zhang, M., Proweller, A., Tu, L., Parmacek, M.S., Pear, W.S., Epstein, J.A. J. Clin. Invest. (2007) [Pubmed]
  7. Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas. Spaulding, C., Reschly, E.J., Zagort, D.E., Yashiro-Ohtani, Y., Beverly, L.J., Capobianco, A., Pear, W.S., Kee, B.L. Blood (2007) [Pubmed]
  8. Long-lasting induction of Notch2 in the hippocampus of kainate-treated adult mice. Toninelli, G.F., Bernardi, C., Quarto, M., Lozza, G., Memo, M., Grilli, M. Neuroreport (2003) [Pubmed]
  9. Learning and memory deficits in Notch mutant mice. Costa, R.M., Honjo, T., Silva, A.J. Curr. Biol. (2003) [Pubmed]
  10. Expression analysis of a Notch homologue in the mouse embryo. Reaume, A.G., Conlon, R.A., Zirngibl, R., Yamaguchi, T.P., Rossant, J. Dev. Biol. (1992) [Pubmed]
  11. Notch signalling regulates stem cell numbers in vitro and in vivo. Androutsellis-Theotokis, A., Leker, R.R., Soldner, F., Hoeppner, D.J., Ravin, R., Poser, S.W., Rueger, M.A., Bae, S.K., Kittappa, R., McKay, R.D. Nature (2006) [Pubmed]
  12. The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Adhikary, S., Marinoni, F., Hock, A., Hulleman, E., Popov, N., Beier, R., Bernard, S., Quarto, M., Capra, M., Goettig, S., Kogel, U., Scheffner, M., Helin, K., Eilers, M. Cell (2005) [Pubmed]
  13. Instability of Hes7 protein is crucial for the somite segmentation clock. Hirata, H., Bessho, Y., Kokubu, H., Masamizu, Y., Yamada, S., Lewis, J., Kageyama, R. Nat. Genet. (2004) [Pubmed]
  14. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Amsen, D., Blander, J.M., Lee, G.R., Tanigaki, K., Honjo, T., Flavell, R.A. Cell (2004) [Pubmed]
  15. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. Searfoss, G.H., Jordan, W.H., Calligaro, D.O., Galbreath, E.J., Schirtzinger, L.M., Berridge, B.R., Gao, H., Higgins, M.A., May, P.C., Ryan, T.P. J. Biol. Chem. (2003) [Pubmed]
  16. Gleevec inhibits beta-amyloid production but not Notch cleavage. Netzer, W.J., Dou, F., Cai, D., Veach, D., Jean, S., Li, Y., Bornmann, W.G., Clarkson, B., Xu, H., Greengard, P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  17. Pertussis toxin can replace T cell receptor signals that induce positive selection of CD8 T cells. Takahama, Y., Tokoro, Y., Sugawara, T., Negishi, I., Nakauchi, H. Eur. J. Immunol. (1997) [Pubmed]
  18. Notch signaling is essential for vascular morphogenesis in mice. Krebs, L.T., Xue, Y., Norton, C.R., Shutter, J.R., Maguire, M., Sundberg, J.P., Gallahan, D., Closson, V., Kitajewski, J., Callahan, R., Smith, G.H., Stark, K.L., Gridley, T. Genes Dev. (2000) [Pubmed]
  19. p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Devgan, V., Mammucari, C., Millar, S.E., Brisken, C., Dotto, G.P. Genes Dev. (2005) [Pubmed]
  20. Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization. Huang, E.J., Li, H., Tang, A.A., Wiggins, A.K., Neve, R.L., Zhong, W., Jan, L.Y., Jan, Y.N. Genes Dev. (2005) [Pubmed]
  21. Notch signalling pathway mediates hair cell development in mammalian cochlea. Lanford, P.J., Lan, Y., Jiang, R., Lindsell, C., Weinmaster, G., Gridley, T., Kelley, M.W. Nat. Genet. (1999) [Pubmed]
  22. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Wong, P.C., Zheng, H., Chen, H., Becher, M.W., Sirinathsinghji, D.J., Trumbauer, M.E., Chen, H.Y., Price, D.L., Van der Ploeg, L.H., Sisodia, S.S. Nature (1997) [Pubmed]
  23. Pax5 promotes B lymphopoiesis and blocks T cell development by repressing Notch1. Souabni, A., Cobaleda, C., Schebesta, M., Busslinger, M. Immunity (2002) [Pubmed]
  24. Cortisol regulates the expression of Notch in osteoblasts. Pereira, R.M., Delany, A.M., Durant, D., Canalis, E. J. Cell. Biochem. (2002) [Pubmed]
  25. Testosterone influenced the expression of Notch1, Notch2 and Jagged1 induced by lipopolysaccharide in macrophages. Guo, D., Zhang, H., Liu, L., Wang, L., Cheng, Y., Qiao, Z. Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie. (2004) [Pubmed]
  26. Unique patterns of Notch1, Notch4 and Jagged1 expression in ovarian vessels during folliculogenesis and corpus luteum formation. Vorontchikhina, M.A., Zimmermann, R.C., Shawber, C.J., Tang, H., Kitajewski, J. Gene Expr. Patterns (2005) [Pubmed]
  27. Notch1 and Jagged1 are expressed after CNS demyelination, but are not a major rate-determining factor during remyelination. Stidworthy, M.F., Genoud, S., Li, W.W., Leone, D.P., Mantei, N., Suter, U., Franklin, R.J. Brain (2004) [Pubmed]
  28. Corneal epithelial cell fate is maintained during repair by Notch1 signaling via the regulation of vitamin A metabolism. Vauclair, S., Majo, F., Durham, A.D., Ghyselinck, N.B., Barrandon, Y., Radtke, F. Dev. Cell (2007) [Pubmed]
  29. Downregulation by lipopolysaccharide of Notch signaling, via nitric oxide. Kim, M.Y., Park, J.H., Mo, J.S., Ann, E.J., Han, S.O., Baek, S.H., Kim, K.J., Im, S.Y., Park, J.W., Choi, E.J., Park, H.S. J. Cell. Sci. (2008) [Pubmed]
  30. Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. Nobta, M., Tsukazaki, T., Shibata, Y., Xin, C., Moriishi, T., Sakano, S., Shindo, H., Yamaguchi, A. J. Biol. Chem. (2005) [Pubmed]
  31. Identification of a stromal cell type characterized by the secretion of a soluble integrin-binding protein, MFG-E8, in mouse early gonadogenesis. Kanai, Y., Kanai-Azuma, M., Tajima, Y., Birk, O.S., Hayashi, Y., Sanai, Y. Mech. Dev. (2000) [Pubmed]
  32. Direct regulation of the Nrarp gene promoter by the Notch signaling pathway. Pirot, P., van Grunsven, L.A., Marine, J.C., Huylebroeck, D., Bellefroid, E.J. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  33. Cell fate determination regulated by a transcriptional signal network in the developing mouse brain. Fukuda, S., Taga, T. Anatomical science international / Japanese Association of Anatomists. (2005) [Pubmed]
  34. p300 is required for MyoD-dependent cell cycle arrest and muscle-specific gene transcription. Puri, P.L., Avantaggiati, M.L., Balsano, C., Sang, N., Graessmann, A., Giordano, A., Levrero, M. EMBO J. (1997) [Pubmed]
  35. Effect of PS1 deficiency and an APP gamma-secretase inhibitor on Notch1 signaling in primary mammalian neurons. Jack, C., Berezovska, O., Wolfe, M.S., Hyman, B.T. Brain Res. Mol. Brain Res. (2001) [Pubmed]
  36. Presenilin-1 D257A and D385A mutants fail to cleave Notch in their endoproteolyzed forms, but only presenilin-1 D385A mutant can restore its gamma-secretase activity with the compensatory overexpression of normal C-terminal fragment. Kim, H., Ki, H., Park, H.S., Kim, K. J. Biol. Chem. (2005) [Pubmed]
  37. Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Minter, L.M., Turley, D.M., Das, P., Shin, H.M., Joshi, I., Lawlor, R.G., Cho, O.H., Palaga, T., Gottipati, S., Telfer, J.C., Kostura, L., Fauq, A.H., Simpson, K., Such, K.A., Miele, L., Golde, T.E., Miller, S.D., Osborne, B.A. Nat. Immunol. (2005) [Pubmed]
  38. Presenilin-1 regulates neuronal differentiation during neurogenesis. Handler, M., Yang, X., Shen, J. Development (2000) [Pubmed]
  39. RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells. Robert-Moreno, A., Espinosa, L., de la Pompa, J.L., Bigas, A. Development (2005) [Pubmed]
  40. Notch-regulated ankyrin-repeat protein inhibits Notch1 signaling: multiple Notch1 signaling pathways involved in T cell development. Yun, T.J., Bevan, M.J. J. Immunol. (2003) [Pubmed]
  41. RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Muraguchi, T., Takegami, Y., Ohtsuka, T., Kitajima, S., Chandana, E.P., Omura, A., Miki, T., Takahashi, R., Matsumoto, N., Ludwig, A., Noda, M., Takahashi, C. Nat. Neurosci. (2007) [Pubmed]
  42. Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A. Fernandez-Martinez, J., Vela, E.M., Tora-Ponsioen, M., Ocaña, O.H., Nieto, M.A., Galceran, J. J. Cell. Sci. (2009) [Pubmed]
  43. Notch1 is essential for postimplantation development in mice. Swiatek, P.J., Lindsell, C.E., del Amo, F.F., Weinmaster, G., Gridley, T. Genes Dev. (1994) [Pubmed]
  44. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Fischer, A., Schumacher, N., Maier, M., Sendtner, M., Gessler, M. Genes Dev. (2004) [Pubmed]
  45. Numb mediates the interaction between Wnt and Notch to modulate primitive erythropoietic specification from the hemangioblast. Cheng, X., Huber, T.L., Chen, V.C., Gadue, P., Keller, G.M. Development (2008) [Pubmed]
  46. Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Hamada, Y., Kadokawa, Y., Okabe, M., Ikawa, M., Coleman, J.R., Tsujimoto, Y. Development (1999) [Pubmed]
  47. Stimulation of osteoblastic cell differentiation by Notch. Tezuka, K., Yasuda, M., Watanabe, N., Morimura, N., Kuroda, K., Miyatani, S., Hozumi, N. J. Bone Miner. Res. (2002) [Pubmed]
  48. Mapping of notch activation during cochlear development in mice: implications for determination of prosensory domain and cell fate diversification. Murata, J., Tokunaga, A., Okano, H., Kubo, T. J. Comp. Neurol. (2006) [Pubmed]
  49. Notch1 and Jagged1 expression by the developing pulmonary vasculature. Taichman, D.B., Loomes, K.M., Schachtner, S.K., Guttentag, S., Vu, C., Williams, P., Oakey, R.J., Baldwin, H.S. Dev. Dyn. (2002) [Pubmed]
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