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Gene Review

NEUROD1  -  neuronal differentiation 1

Homo sapiens

Synonyms: BETA2, BHF-1, BHLHA3, Class A basic helix-loop-helix protein 3, MODY6, ...
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Disease relevance of NEUROD1


Psychiatry related information on NEUROD1


High impact information on NEUROD1

  • The latter include peptides specific for the alpha 7, alpha 3 beta 2, and alpha 3 beta 4 nicotinic receptor subtypes [12].
  • Further analyses reveal three rules for NLS recognition by Kap beta 2: NLSs are structurally disordered in free substrates, have overall basic character, and possess a central hydrophobic or basic motif followed by a C-terminal R/H/KX(2-5)PY consensus sequence [13].
  • The structure of Kap beta 2 (also known as Transportin) bound to one of its substrates, the NLS of hnRNP A1, that we report here explains the mechanism of substrate displacement by Ran GTPase [13].
  • Our findings suggest that deficient binding of NEUROD1 or binding of a transcriptionally inactive NEUROD1 polypeptide to target promoters in pancreatic islets leads to the development of type 2 diabetes in humans [14].
  • The avidity of integrin CR3 (also known as alpha M beta 2, Mac-1, Mo-1, and CD11b/CD18) may be reversibly altered without changes in the number of cell surface receptors [15].

Chemical compound and disease context of NEUROD1


Biological context of NEUROD1


Anatomical context of NEUROD1


Associations of NEUROD1 with chemical compounds

  • In conclusion, we observed a combined effect of variations in NEUROD1, NEUROG3, and TCF1 in contributing to overall glucose intolerance in a South Indian population [25].
  • Four diabetic patients carried the homozygous mutation (Thr/Thr) in the NeuroD1 gene and 3 patients carried the homozygous mutation (Trp/Trp) in the Pax4 gene, while both homozygous mutations were not detected in the control subjects [28].
  • BETA 2/NEUROD1 is a key regulator of pancreatic islet morphogenesis and insulin gene transcription [29].
  • Neuronal nicotinic acetylcholine receptors are pentamers of homomeric or heteromeric combinations of alpha (alpha2-alpha10) and beta (beta2-beta4) subunits, which have different pharmacological and biophysical properties and locations in the brain [30].
  • MCP-1 stimulated beta1 integrin-dependent, but not beta2 integrin-dependent cell adhesion in a time-dependent manner [31].
  • NeuroD1 is inactive in baseline prostate cell lines and BPHs, whereas it is actively expressed in cAMP-treated EPN, PC3, and DU145 cells [32].

Physical interactions of NEUROD1

  • We have identified an INSM1 binding site in the neuroD/beta2 promoter and demonstrated transcriptional repressor activity of INSM1 by transient transfection assay [33].
  • Mutational analysis of a proximal enhancer in the secretin gene identified several cis-acting elements in addition to the E-box binding site for BETA2 [34].
  • ISL1 physically interacts with BETA2 to promote insulin gene transcriptional synergy in non-beta cells [35].
  • Previous studies have shown that PDX-1 can interact synergistically with E47 and beta2 to activate the rat insulin 1 promoter [36].
  • These findings indicate that in addition to induction of CD11a/CD18-mediated cell adhesion, the ICAM-2 peptide may also serve as a "trigger" for high avidity ligand binding of other beta 2 integrins [37].

Enzymatic interactions of NEUROD1

  • Insulin receptor beta subunit autophosphorylation occurs in an intramolecular trans-reaction in which one beta subunit phosphorylates the adjacent beta subunit within an alpha 2 beta 2 holoreceptor complex (Frattali, A. L., Treadway, J. L., and Pessin, J. E. (1992) J. Biol. Chem. 267, 19521-19528) [38].
  • In the present study we identified phospholipase C gamma 2 (PLC gamma 2) as one of the major proteins that was phosphorylated on tyrosine in response to beta 2 integrin activation [39].

Co-localisations of NEUROD1


Regulatory relationships of NEUROD1

  • Cyclin D1 co-operates with INSM1 and suppresses neuroD/beta2 promoter activity [33].
  • In contrast, neutrophil adhesion to fibronectin was completely inhibited by anti-beta2 integrins, suggesting that S100A9-induced specific activation of beta2 integrin is essential to neutrophil adhesion [41].
  • The NeuroD1-containing heterodimers specifically recognize and activate transcription from the POMC promoter E box that confers transcriptional specificity [42].
  • Interestingly, the NeuroD1 heterodimers activate transcription in synergy with Ptx1, a Bicoid-related homeodomain protein, which also contributes to corticotroph specificity of POMC transcription [42].
  • BETA2 activates transcription from the upstream glucokinase gene promoter in islet beta-cells and gut endocrine cells [43].

Other interactions of NEUROD1


Analytical, diagnostic and therapeutic context of NEUROD1


  1. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type II diabetes in France. Dupont, S., Vionnet, N., Chèvre, J.C., Gallina, S., Dina, C., Seino, Y., Yamada, Y., Froguel, P. Diabetologia (1999) [Pubmed]
  2. Diagnostic screening of NEUROD1 (MODY6) in subjects with MODY or gestational diabetes mellitus. Sagen, J.V., Baumann, M.E., Salvesen, H.B., Molven, A., Søvik, O., Njølstad, P.R. Diabet. Med. (2005) [Pubmed]
  3. Expression of neurogenic basic helix-loop-helix genes in primitive neuroectodermal tumors. Rostomily, R.C., Bermingham-McDonogh, O., Berger, M.S., Tapscott, S.J., Reh, T.A., Olson, J.M. Cancer Res. (1997) [Pubmed]
  4. Protein Kinase C {beta} Enhances Growth and Expression of Cyclin D1 in Human Breast Cancer Cells. Li, H., Weinstein, I.B. Cancer Res. (2006) [Pubmed]
  5. NEUROD polymorphism Ala45Thr is associated with Type 1 diabetes mellitus in Czech children. Cinek, O., Drevínek, P., Sumník, Z., Bendlová, B., Sedláková, P., Kolousková, S., Snajderová, M., Vavrinec, J. Diabetes Res. Clin. Pract. (2003) [Pubmed]
  6. Methylated NEUROD1 promoter is a marker for chemosensitivity in breast cancer. Fiegl, H., Jones, A., Hauser-Kronberger, C., Hutarew, G., Reitsamer, R., Jones, R.L., Dowsett, M., Mueller-Holzner, E., Windbichler, G., Daxenbichler, G., Goebel, G., Ensinger, C., Jacobs, I., Widschwendter, M. Clin. Cancer Res. (2008) [Pubmed]
  7. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Bremner, J.D., Innis, R.B., Ng, C.K., Staib, L.H., Salomon, R.M., Bronen, R.A., Duncan, J., Southwick, S.M., Krystal, J.H., Rich, D., Zubal, G., Dey, H., Soufer, R., Charney, D.S. Arch. Gen. Psychiatry (1997) [Pubmed]
  8. Adrenergic receptors in Alzheimer's disease brain: selective increases in the cerebella of aggressive patients. Russo-Neustadt, A., Cotman, C.W. J. Neurosci. (1997) [Pubmed]
  9. Beta 2-receptor density on mononuclear blood cells in patients suffering from neuroleptic-induced akathisia (NIA). Botschev, C., Bondy, B., Hofmann, M., Kircher, T., Müller-Spahn, F. Biol. Psychiatry (1996) [Pubmed]
  10. Effects of beta 1- and beta 2-blockade on blood pressure and sympathetic responses to flight phobia stress. Ekeberg, O., Kjeldsen, S.E., Eide, I.K., Greenwood, D.T., Enger, E. Clin. Pharmacol. Ther. (1990) [Pubmed]
  11. Selective nicotinic acetylcholine receptor subunit deficits identified in Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies by immunoprecipitation. Gotti, C., Moretti, M., Bohr, I., Ziabreva, I., Vailati, S., Longhi, R., Riganti, L., Gaimarri, A., McKeith, I.G., Perry, R.H., Aarsland, D., Larsen, J.P., Sher, E., Beattie, R., Clementi, F., Court, J.A. Neurobiol. Dis. (2006) [Pubmed]
  12. Conus peptides targeted to specific nicotinic acetylcholine receptor subtypes. McIntosh, J.M., Santos, A.D., Olivera, B.M. Annu. Rev. Biochem. (1999) [Pubmed]
  13. Rules for nuclear localization sequence recognition by karyopherin beta 2. Lee, B.J., Cansizoglu, A.E., Süel, K.E., Louis, T.H., Zhang, Z., Chook, Y.M. Cell (2006) [Pubmed]
  14. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Malecki, M.T., Jhala, U.S., Antonellis, A., Fields, L., Doria, A., Orban, T., Saad, M., Warram, J.H., Montminy, M., Krolewski, A.S. Nat. Genet. (1999) [Pubmed]
  15. Integrin modulating factor-1: a lipid that alters the function of leukocyte integrins. Hermanowski-Vosatka, A., Van Strijp, J.A., Swiggard, W.J., Wright, S.D. Cell (1992) [Pubmed]
  16. Hypokalemia from beta2-receptor stimulation by circulating epinephrine. Brown, M.J., Brown, D.C., Murphy, M.B. N. Engl. J. Med. (1983) [Pubmed]
  17. Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. Widschwendter, M., Berger, J., Hermann, M., Müller, H.M., Amberger, A., Zeschnigk, M., Widschwendter, A., Abendstein, B., Zeimet, A.G., Daxenbichler, G., Marth, C. J. Natl. Cancer Inst. (2000) [Pubmed]
  18. Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of beta2 integrin gene expression. Kong, T., Eltzschig, H.K., Karhausen, J., Colgan, S.P., Shelley, C.S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  19. Anti-beta2 glycoprotein I (beta2GPI) autoantibodies recognize an epitope on the first domain of beta2GPI. Iverson, G.M., Victoria, E.J., Marquis, D.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  20. Effects of stress and beta-blockade on platelet function. Hjemdahl, P., Larsson, P.T., Wallén, N.H. Circulation (1991) [Pubmed]
  21. Lack of association of the Ala(45)Thr polymorphism and other common variants of the NeuroD gene with type 1 diabetes. Vella, A., Howson, J.M., Barratt, B.J., Twells, R.C., Rance, H.E., Nutland, S., Tuomilehto-Wolf, E., Tuomilehto, J., Undlien, D.E., Rønningen, K.S., Guja, C., Ionescu-Tîrgovişte, C., Savage, D.A., Todd, J.A. Diabetes (2004) [Pubmed]
  22. The proneural genes NEUROD1 and NEUROD2 are expressed during human trophoblast invasion. Westerman, B.A., Poutsma, A., Maruyama, K., Schrijnemakers, H.F., van Wijk, I.J., Oudejans, C.B. Mech. Dev. (2002) [Pubmed]
  23. The Ala45Thr polymorphism of NEUROD1 is associated with type 1 diabetes in Brazilian women. Oliveira, C.S., Hauache, O.M., Vieira, J.G., Maciel, R.M., Sjöroos, M., Canani, L.H., Velho, G., Gross, J.L., Reis, A.F. Diabetes Metab. (2005) [Pubmed]
  24. NEUROD1 acts in vitro as an upstream regulator of NEUROD2 in trophoblast cells. Westerman, B.A., Chhatta, A., Poutsma, A., van Vegchel, T., Oudejans, C.B. Biochim. Biophys. Acta (2004) [Pubmed]
  25. Polymorphic variations in the neurogenic differentiation-1, neurogenin-3, and hepatocyte nuclear factor-1alpha genes contribute to glucose intolerance in a South Indian population. Jackson, A.E., Cassell, P.G., North, B.V., Vijayaraghavan, S., Gelding, S.V., Ramachandran, A., Snehalatha, C., Hitman, G.A. Diabetes (2004) [Pubmed]
  26. A novel type of PTD, common helix-loop-helix motif, could efficiently mediate protein transduction into mammalian cells. Chen, J., Li, G., Lu, J., Chen, L., Huang, Y., Wu, H., Zhang, J., Lu, D. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  27. The role of BETA2/NeuroD1 in the development of the nervous system. Cho, J.H., Tsai, M.J. Mol. Neurobiol. (2004) [Pubmed]
  28. Beta-cell dysfunction in late-onset diabetic subjects carrying homozygous mutation in transcription factors NeuroD1 and Pax4. Kanatsuka, A., Tokuyama, Y., Nozaki, O., Matsui, K., Egashira, T. Metab. Clin. Exp. (2002) [Pubmed]
  29. Absence of replication in the French population of the association between beta 2/NEUROD-A45T polymorphism and type 1 diabetes. Dupont, S., Dina, C., Hani, E.H., Froguel, P. Diabetes Metab. (1999) [Pubmed]
  30. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Gotti, C., Zoli, M., Clementi, F. Trends Pharmacol. Sci. (2006) [Pubmed]
  31. Distinct signaling pathways for MCP-1-dependent integrin activation and chemotaxis. Ashida, N., Arai, H., Yamasaki, M., Kita, T. J. Biol. Chem. (2001) [Pubmed]
  32. NeuroD1 expression in human prostate cancer: can it contribute to neuroendocrine differentiation comprehension? Cindolo, L., Franco, R., Cantile, M., Schiavo, G., Liguori, G., Chiodini, P., Salzano, L., Autorino, R., Di Blasi, A., Falsaperla, M., Feudale, E., Botti, G., Gallo, A., Cillo, C. Eur. Urol. (2007) [Pubmed]
  33. INSM1 functions as a transcriptional repressor of the neuroD/beta2 gene through the recruitment of cyclin D1 and histone deacetylases. Liu, W.D., Wang, H.W., Muguira, M., Breslin, M.B., Lan, M.S. Biochem. J. (2006) [Pubmed]
  34. Novel transcriptional potentiation of BETA2/NeuroD on the secretin gene promoter by the DNA-binding protein Finb/RREB-1. Ray, S.K., Nishitani, J., Petry, M.W., Fessing, M.Y., Leiter, A.B. Mol. Cell. Biol. (2003) [Pubmed]
  35. ISL1 physically interacts with BETA2 to promote insulin gene transcriptional synergy in non-beta cells. Peng, S.Y., Wang, W.P., Meng, J., Li, T., Zhang, H., Li, Y.M., Chen, P., Ma, K.T., Zhou, C.Y. Biochim. Biophys. Acta (2005) [Pubmed]
  36. Relative contribution of PDX-1, MafA and E47/beta2 to the regulation of the human insulin promoter. Docherty, H.M., Hay, C.W., Ferguson, L.A., Barrow, J., Durward, E., Docherty, K. Biochem. J. (2005) [Pubmed]
  37. A peptide derived from the intercellular adhesion molecule-2 regulates the avidity of the leukocyte integrins CD11b/CD18 and CD11c/CD18. Li, R., Xie, J., Kantor, C., Koistinen, V., Altieri, D.C., Nortamo, P., Gahmberg, C.G. J. Cell Biol. (1995) [Pubmed]
  38. Relationship between alpha subunit ligand occupancy and beta subunit autophosphorylation in insulin/insulin-like growth factor-1 hybrid receptors. Frattali, A.L., Pessin, J.E. J. Biol. Chem. (1993) [Pubmed]
  39. Ca2+ signalling mechanisms of the beta 2 integrin on neutrophils: involvement of phospholipase C gamma 2 and Ins(1,4,5)P3. Hellberg, C., Molony, L., Zheng, L., Andersson, T. Biochem. J. (1996) [Pubmed]
  40. The NeuroD1/BETA2 sequences essential for insulin gene transcription colocalize with those necessary for neurogenesis and p300/CREB binding protein binding. Sharma, A., Moore, M., Marcora, E., Lee, J.E., Qiu, Y., Samaras, S., Stein, R. Mol. Cell. Biol. (1999) [Pubmed]
  41. S100A9 mediates neutrophil adhesion to fibronectin through activation of beta2 integrins. Anceriz, N., Vandal, K., Tessier, P.A. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  42. NeuroD1/beta2 contributes to cell-specific transcription of the proopiomelanocortin gene. Poulin, G., Turgeon, B., Drouin, J. Mol. Cell. Biol. (1997) [Pubmed]
  43. BETA2 activates transcription from the upstream glucokinase gene promoter in islet beta-cells and gut endocrine cells. Moates, J.M., Nanda, S., Cissell, M.A., Tsai, M.J., Stein, R. Diabetes (2003) [Pubmed]
  44. Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter. Glick, E., Leshkowitz, D., Walker, M.D. J. Biol. Chem. (2000) [Pubmed]
  45. cDNA cloning and expression analysis of NeuroD mRNA in human retina. Acharya, H.R., Dooley, C.M., Thoreson, W.B., Ahmad, I. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  46. Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1. Ferretti, E., Di Stefano, D., Zazzeroni, F., Gallo, R., Fratticci, A., Carfagnini, R., Angiulli, S., Santoro, A., Minniti, G., Tamburrano, G., Alesse, E., Cantore, G., Gulino, A., Jaffrain-Rea, M.L. J. Endocrinol. Invest. (2003) [Pubmed]
  47. The Ala45Thr polymorphism of BETA2/NeuroD1 gene and susceptibility to type 1 diabetes mellitus in caucasians. Malecki, M.T., Klupa, T., Moczulski, D.K., Rogus, J.J. Exp. Clin. Endocrinol. Diabetes (2003) [Pubmed]
  48. Ala45Thr polymorphism of the NEUROD1 gene and diabetes susceptibility: a meta-analysis. Kavvoura, F.K., Ioannidis, J.P. Hum. Genet. (2005) [Pubmed]
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