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Gene Review

Notch4  -  notch 4

Mus musculus

Synonyms: Int-3, Int3, N4, Neurogenic locus notch homolog protein 4, Notch 4
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Disease relevance of Notch4

  • Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice [1].
  • Expression of Notch4(int-3), a truncated form of Notch4 having most of its extracellular domain deleted, as a transgene in mice induces the formation of poorly differentiated mammary carcinomas [2].
  • Here we show that blood flow recovery and postnatal neovascularization in response to hindlimb ischemia in haploinsufficient global or endothelial-specific Notch1(+/-) mice, but not Notch4(-/-) mice, were impaired compared with wild-type mice [3].
  • Insertional mutation of the Int3 gene, a member of the Notch gene family, is frequently associated with primary mouse mammary tumors induced by the mouse mammary tumor virus (MMTV) [4].
  • A novel non-mouse mammary tumor virus activation of the Int-3 gene in a spontaneous mouse mammary tumor [5].

High impact information on Notch4

  • However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene [6].
  • We expressed a constitutively active Notch4, int3, in the adult mouse endothelium by using the tetracycline-repressible system to suppress int3 during embryogenesis. int3 caused profound blood vessel enlargement and AV shunting, which are hallmarks of AVM, and led to lethality within weeks of its expression [1].
  • Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium [7].
  • In transgenic livers, we showed that DLL4, active Notch4, and ephrin B2 were gradually up-regulated within the hepatocarcinoma progression and expressed on tumor sinusoidal endothelial cells [8].
  • Expression of a truncated Int3 gene in developing secretory mammary epithelium specifically retards lobular differentiation resulting in tumorigenesis [4].

Biological context of Notch4

  • Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos [6].
  • We also showed that the activation of Notch4 is required for VEGF-induced up-regulation of ephrin B2 and the differentiation of human venous endothelial cells in vitro [8].
  • 9, that developed in a BALB/c mouse, we have found an insertion of a 1.2-kb sequence, consisting of a 5' long terminal repeat and gag sequences of an intracisternal type A particle (IAP) as well as an extra copy of the Notch4/int3 genomic sequences containing exons 23 and 24, into the intron between exons 24 and 25 of the Notch4/int3 gene [9].
  • The int3 oncogene was discovered as a frequent target in mouse mammary tumor virus-induced mammary tumors and encodes the intracellular domain of a Notch4/int3 protein [9].
  • The protein encoded by the Notch4 gene is a member of the Notch/lin-12 family of transmembrane receptor proteins, which have been shown to control cell fate determination and cell differentiation in a wide variety of organisms [2].

Anatomical context of Notch4

  • Surprisingly, directed expression of a constitutively active form of Notch4 within mouse endothelial cells produces a similar vascular embryonic lethality [10].
  • RESULTS: Macrophage precursors expressed high levels of Notch1 transcript, while maturing macrophages expressed high levels of both Notch1 and Notch4 [11].
  • Notch4 and Dll-4 mRNAs are synthesized from the 2-cell through to the hatched blastocyst stage [12].
  • These results were attributed to a gain of function modification of the Int3 gene, which led to a restriction of cell fate selection in the affected mammary epithelial cells [4].
  • Previous studies have demonstrated that mammary gland development and function was severely impaired in transgenic mice expressing the truncated Int3 gene product from the MMTV viral promoter [4].

Associations of Notch4 with chemical compounds

  • Here, we characterize the expression patterns of Notch1, Notch4, and Jagged1 proteins during the process of folliculogenesis and corpus luteum formation in the mouse ovary, an organ with dynamic physiological angiogenic growth [13].

Regulatory relationships of Notch4


Other interactions of Notch4


Analytical, diagnostic and therapeutic context of Notch4


  1. Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Carlson, T.R., Yan, Y., Wu, X., Lam, M.T., Tang, G.L., Beverly, L.J., Messina, L.M., Capobianco, A.J., Werb, Z., Wang, R. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Expression of an activated Notch4(int-3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro. Soriano, J.V., Uyttendaele, H., Kitajewski, J., Montesano, R. Int. J. Cancer (2000) [Pubmed]
  3. Critical role of endothelial Notch1 signaling in postnatal angiogenesis. Takeshita, K., Satoh, M., Ii, M., Silver, M., Limbourg, F.P., Mukai, Y., Rikitake, Y., Radtke, F., Gridley, T., Losordo, D.W., Liao, J.K. Circ. Res. (2007) [Pubmed]
  4. Expression of a truncated Int3 gene in developing secretory mammary epithelium specifically retards lobular differentiation resulting in tumorigenesis. Gallahan, D., Jhappan, C., Robinson, G., Hennighausen, L., Sharp, R., Kordon, E., Callahan, R., Merlino, G., Smith, G.H. Cancer Res. (1996) [Pubmed]
  5. A novel non-mouse mammary tumor virus activation of the Int-3 gene in a spontaneous mouse mammary tumor. Kordon, E.C., Smith, G.H., Callahan, R., Gallahan, D. J. Virol. (1995) [Pubmed]
  6. 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]
  7. Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Uyttendaele, H., Ho, J., Rossant, J., Kitajewski, J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  8. The Role of the Vascular Endothelial Growth Factor-Delta-like 4 Ligand/Notch4-Ephrin B2 Cascade in Tumor Vessel Remodeling and Endothelial Cell Functions. Hainaud, P., Contrerès, J.O., Villemain, A., Liu, L.X., Plouët, J., Tobelem, G., Dupuy, E. Cancer Res. (2006) [Pubmed]
  9. Intracisternal type A particle-mediated activation of the Notch4/int3 gene in a mouse mammary tumor: generation of truncated Notch4/int3 mRNAs by retroviral splicing events. Lee, J.S., Haruna, T., Ishimoto, A., Honjo, T., Yanagawa, S. J. Virol. (1999) [Pubmed]
  10. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Villa, N., Walker, L., Lindsell, C.E., Gasson, J., Iruela-Arispe, M.L., Weinmaster, G. Mech. Dev. (2001) [Pubmed]
  11. Expression of notch receptors, notch ligands, and fringe genes in hematopoiesis. Singh, N., Phillips, R.A., Iscove, N.N., Egan, S.E. Exp. Hematol. (2000) [Pubmed]
  12. Developmental expression of the Notch signaling pathway genes during mouse preimplantation development. Cormier, S., Vandormael-Pournin, S., Babinet, C., Cohen-Tannoudji, M. Gene Expr. Patterns (2004) [Pubmed]
  13. 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]
  14. Kit and PDGFR-alpha activities are necessary for Notch4/Int3-induced tumorigenesis. Raafat, A., Zoltan-Jones, A., Strizzi, L., Bargo, S., Kimura, K., Salomon, D., Callahan, R. Oncogene (2007) [Pubmed]
  15. Glucocorticoid and growth factor synergism requirement for Notch4 chromatin domain activation. Wu, J., Bresnick, E.H. Mol. Cell. Biol. (2007) [Pubmed]
  16. Notch gene expression during pancreatic organogenesis. Lammert, E., Brown, J., Melton, D.A. Mech. Dev. (2000) [Pubmed]
  17. Understanding mammary gland development through the imbalanced expression of growth regulators. Robinson, G.W., Smith, G.H., Gallahan, D., Zimmer, A., Furth, P.A., Hennighausen, L. Dev. Dyn. (1996) [Pubmed]
  18. Proto-oncogene of int-3, a mouse Notch homologue, is expressed in endothelial cells during early embryogenesis. Shirayoshi, Y., Yuasa, Y., Suzuki, T., Sugaya, K., Kawase, E., Ikemura, T., Nakatsuji, N. Genes Cells (1997) [Pubmed]
  19. Molecular cloning of delta-4, a new mouse and human Notch ligand. Yoneya, T., Tahara, T., Nagao, K., Yamada, Y., Yamamoto, T., Osawa, M., Miyatani, S., Nishikawa, M. J. Biochem. (2001) [Pubmed]
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