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Gene Review

Hes1  -  hairy and enhancer of split 1 (Drosophila)

Mus musculus

Synonyms: Hairy and enhancer of split 1, Hes-1, Hry, Transcription factor HES-1, bHLHb39
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Disease relevance of Hes1

  • Furthermore, misexpression of Hes3b with retrovirus in neural precursor cells inhibits neuronal differentiation like Hes1, whereas Hes3a does not [1].
  • The downstream target gene Hes1 was transcribed in a lymphoma with insertion of murine leukemia virus, but not in a lymphoma with a 5' deletion [2].
  • Here, we found that misexpression of Hes1 in the developing retina promotes formation of undifferentiated precursor-like cells, whereas in Hes1-null retina, precursors are not properly maintained and prematurely differentiate into ganglion cells [3].
  • It is of interest to note that Hes-1 expression, a downstream target of Notch signaling pathway, was significantly decreased by Salmonella infection [4].

High impact information on Hes1

  • Here we show that mice deficient in Hes1 (encoding Hes-1) display severe pancreatic hypoplasia caused by depletion of pancreatic epithelial precursors due to accelerated differentiation of post-mitotic endocrine cells expressing glucagon [5].
  • Moreover, upregulation of several bHLH components is associated with precocious and excessive differentiation of multiple endocrine cell types in the developing stomach and gut, showing that Hes-1 operates as a general negative regulator of endodermal endocrine differentiation [5].
  • The bHLH gene Hes1 is essential for expansion of early T cell precursors [6].
  • Transfer of Hes1-null fetal liver cells into RAG2-null host mice normally reconstitutes B cells but fails to generate mature T cells in the thymus [6].
  • Mice mutant for the bHLH gene Hes1, which is known to keep cells in a proliferative state, mostly lack thymus [6].

Biological context of Hes1


Anatomical context of Hes1

  • During ductal plate remodeling, Notch2 and Hes1 were up-regulated exclusively in the biliary epithelial cells that form tubular structures [8].
  • The hepatocyte maturation level and IHBD development were studied in Hes1 null mice in comparison with wild-type mice [8].
  • It is thought that small intestinal epithelial stem cell progeny, via Notch signaling, yield a Hes1-expressing columnar lineage progenitor and an Atoh1 (also known as Math1)-expressing common progenitor for all granulocytic lineages including enteroendocrine cells, one of the body's largest populations of endocrine cells [11].
  • Recombinant Lunatic fringe protein induced Hes1 expression in the dental epithelium, suggesting that Lunatic fringe can act also extracellularly [12].
  • Notch1/2/3 and Hes1 were expressed in most GC cell lines as well as normal gastric mucosae, while Hes2/3 were expressed in neither these cell lines nor the normal stomach [13].

Associations of Hes1 with chemical compounds

  • These data show that Hes1 and Hes5 expression are independently regulated along the proximal-distal axis of the developing nephron [14].
  • In embryonic carcinoma cells, endogenous Hes1 expression was repressed by retinoic acid in concord with enhanced p27(Kip1) expression and cell cycle arrest [15].
  • Additional studies in 3T3-L1 preadipocytes demonstrate that this FGSI inhibits Hes-1 expression while up-regulating adipsin expression [16].

Enzymatic interactions of Hes1

  • Neither Hes1 (hairy and enhancer of split) nor Hes5 appeared to mediate gp130-enhanced NOTCH1 signaling that regulates NSC maintenance [17].

Regulatory relationships of Hes1

  • The expression of Lunatic fringe and Hes1 depended on mesenchymal signals and both were positively regulated by FGF-10 [12].
  • Hes5 synergizes with Hes1 and regulates neurogenesis at the level of Ngn1 expression [18].
  • Polycomb group gene mel-18 regulates early T progenitor expansion by maintaining the expression of Hes-1, a target of the Notch pathway [19].
  • In addition, mel-18(-/-) T precursors could not maintain the Hes-1 expression induced by Delta-like-1 in monolayer culture [19].

Other interactions of Hes1

  • We also examined the morphological appearance of kidneys from mice where the Hes1 or Hes5 genes were deleted and found that at least at the gross morphological level, there was little difference from wild-type kidneys [20].
  • Mutational analysis of Hes1 (Nat. Genet. 24 (2000) 36) and Math1 (Science 294 (2001) 2155) have implicated Notch signalling in the regulation of intestinal epithelium development and homeostasis [21].
  • Overexpression of Lfng did not affect spatial or temporal expression of Hes1 and Mash-1 [22].
  • We have examined the embryonic and postnatal expression of the Hes1 and Hes3 genes as well as all four murine Grgs in order to determine where spatial and temporal overlaps of Hes and Grg corepressors may occur [23].
  • In S-shaped bodies, Hes1 expression was detected in the middle part which gives rise to the proximal tubule, but also extended into the lower and upper parts which give rise to the glomerulus and distal tubule, respectively, and was similar to the proximal-distal expression patterns for Notch1 and Jagged1 in these nephrogenic structures [14].

Analytical, diagnostic and therapeutic context of Hes1


  1. Generation of structurally and functionally distinct factors from the basic helix-loop-helix gene Hes3 by alternative first exons. Hirata, H., Ohtsuka, T., Bessho, Y., Kageyama, R. J. Biol. Chem. (2000) [Pubmed]
  2. Radiation-induced deletions in the 5' end region of Notch1 lead to the formation of truncated proteins and are involved in the development of mouse thymic lymphomas. Tsuji, H., Ishii-Ohba, H., Ukai, H., Katsube, T., Ogiu, T. Carcinogenesis (2003) [Pubmed]
  3. Roles of the bHLH gene Hes1 in retinal morphogenesis. Takatsuka, K., Hatakeyama, J., Bessho, Y., Kageyama, R. Brain Res. (2004) [Pubmed]
  4. Presence of presenilin 1/2 affects the invasion and replication of Salmonella typhimurium. Park, J.H., Kim, H.J., Choy, H.E., Kim, K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  5. Control of endodermal endocrine development by Hes-1. Jensen, J., Pedersen, E.E., Galante, P., Hald, J., Heller, R.S., Ishibashi, M., Kageyama, R., Guillemot, F., Serup, P., Madsen, O.D. Nat. Genet. (2000) [Pubmed]
  6. The bHLH gene Hes1 is essential for expansion of early T cell precursors. Tomita, K., Hattori, M., Nakamura, E., Nakanishi, S., Minato, N., Kageyama, R. Genes Dev. (1999) [Pubmed]
  7. Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Kamakura, S., Oishi, K., Yoshimatsu, T., Nakafuku, M., Masuyama, N., Gotoh, Y. Nat. Cell Biol. (2004) [Pubmed]
  8. The role of notch signaling in the development of intrahepatic bile ducts. Kodama, Y., Hijikata, M., Kageyama, R., Shimotohno, K., Chiba, T. Gastroenterology (2004) [Pubmed]
  9. Basic helix-loop-helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium. Ito, T., Udaka, N., Yazawa, T., Okudela, K., Hayashi, H., Sudo, T., Guillemot, F., Kageyama, R., Kitamura, H. Development (2000) [Pubmed]
  10. NGF controls dendrite development in hippocampal neurons by binding to p75NTR and modulating the cellular targets of Notch. Salama-Cohen, P., Arévalo, M.A., Meier, J., Grantyn, R., Rodríguez-Tébar, A. Mol. Biol. Cell (2005) [Pubmed]
  11. Neurogenin 3 and the enteroendocrine cell lineage in the adult mouse small intestinal epithelium. Bjerknes, M., Cheng, H. Dev. Biol. (2006) [Pubmed]
  12. Lunatic fringe, FGF, and BMP regulate the Notch pathway during epithelial morphogenesis of teeth. Mustonen, T., Tümmers, M., Mikami, T., Itoh, N., Zhang, N., Gridley, T., Thesleff, I. Dev. Biol. (2002) [Pubmed]
  13. Hath1 up-regulates gastric mucin gene expression in gastric cells. Sekine, A., Akiyama, Y., Yanagihara, K., Yuasa, Y. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  14. Expression of Hairy/Enhancer of Split genes, Hes1 and Hes5, during murine nephron morphogenesis. Piscione, T.D., Wu, M.Y., Quaggin, S.E. Gene Expr. Patterns (2004) [Pubmed]
  15. Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1. Murata, K., Hattori, M., Hirai, N., Shinozuka, Y., Hirata, H., Kageyama, R., Sakai, T., Minato, N. Mol. Cell. Biol. (2005) [Pubmed]
  16. 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]
  17. Glycoprotein 130 signaling regulates Notch1 expression and activation in the self-renewal of mammalian forebrain neural stem cells. Chojnacki, A., Shimazaki, T., Gregg, C., Weinmaster, G., Weiss, S. J. Neurosci. (2003) [Pubmed]
  18. Hes genes regulate sequential stages of neurogenesis in the olfactory epithelium. Cau, E., Gradwohl, G., Casarosa, S., Kageyama, R., Guillemot, F. Development (2000) [Pubmed]
  19. Polycomb group gene mel-18 regulates early T progenitor expansion by maintaining the expression of Hes-1, a target of the Notch pathway. Miyazaki, M., Kawamoto, H., Kato, Y., Itoi, M., Miyazaki, K., Masuda, K., Tashiro, S., Ishihara, H., Igarashi, K., Amagai, T., Kanno, R., Kanno, M. J. Immunol. (2005) [Pubmed]
  20. Segmental expression of Notch and Hairy genes in nephrogenesis. Chen, L., Al-Awqati, Q. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  21. Expression of Notch pathway components in fetal and adult mouse small intestine. Schröder, N., Gossler, A. Gene Expr. Patterns (2002) [Pubmed]
  22. Overexpression of lunatic fringe does not affect epithelial cell differentiation in the developing mouse lung. van Tuyl, M., Groenman, F., Kuliszewski, M., Ridsdale, R., Wang, J., Tibboel, D., Post, M. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  23. A comparison of Notch, Hes and Grg expression during murine embryonic and post-natal development. Allen, T., Lobe, C.G. Cell. Mol. Biol. (Noisy-le-grand) (1999) [Pubmed]
  24. Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear. Zine, A., Aubert, A., Qiu, J., Therianos, S., Guillemot, F., Kageyama, R., de Ribaupierre, F. J. Neurosci. (2001) [Pubmed]
  25. Hes1 is a negative regulator of inner ear hair cell differentiation. Zheng, J.L., Shou, J., Guillemot, F., Kageyama, R., Gao, W.Q. Development (2000) [Pubmed]
  26. The vitamin D receptor, Runx2, and the Notch signaling pathway cooperate in the transcriptional regulation of osteopontin. Shen, Q., Christakos, S. J. Biol. Chem. (2005) [Pubmed]
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