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Gene Review

Bhlhe23  -  basic helix-loop-helix family, member e23

Mus musculus

Synonyms: A930001L02Rik, BETA4, Bhlhb4, Class B basic helix-loop-helix protein 4, Class E basic helix-loop-helix protein 23, ...
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Disease relevance of Bhlhb4

  • Electroretinograms (ERGs) in the adult Bhlhb4 knockout (Bhlhb4(-/-)) showed that the loss of Bhlhb4 resulted in disrupted rod signaling and profound retinal dysfunction resembling human congenital stationary night blindness (CSNB), characterized by the loss of the scotopic ERG b-wave [1].
  • These results indicate that beta 4 integrin promotes tumor progression by amplifying ErbB2 signaling and identify beta 4 as a potential target for molecular therapy of breast cancer [2].
  • Using recombinant protein kinase C adenoviruses, overexpression of protein kinase Cdelta but not protein kinase Calpha in primary keratinocytes increased beta4 serine phosphorylation, decreased alpha6beta4 localization to the hemidesmosome complexes, and reduced keratinocyte attachment [3].
  • The clustered neuronal nAchRs subunit genes, alpha 3 and beta 4, are expressed in amacrine and ganglion cells where they are used to assemble functional receptor subtypes [4].
  • Targeted expression of alpha6beta4 in the suprabasal layers of transgenic mouse epidermis dramatically increased the frequency of papillomas, carcinomas and metastases induced by chemical carcinogenesis, independent of the beta4 cytoplasmic domain [5].

High impact information on Bhlhb4

  • Ex vivo studies indicate that beta 4 forms a complex with ErbB2 and enhances activation of the transcription factors STAT3 and c-Jun [2].
  • To study the contribution of the integrin alpha 6 beta 4 in hemidesmosome formation and their anchoring properties, we inactivated the beta 4 gene in mice by targeted gene disruption [6].
  • These cells expressed the V alpha 8-J alpha TA72, V beta 4 heterodimer in both progressive infection and protective immunity and across several major histocompatibility haplotypes [7].
  • Recombinant LACK antigen from L. major induced comparable IL-4 production in V beta 4 V alpha 8 CD4+ cells [8].
  • Thus, the IL-4 required for Th2 development and susceptibility to L. major is produced by a restricted population of V beta 4 V alpha 8 CD4+ T cells after cognate interaction with a single antigen from this complex organism [8].

Biological context of Bhlhb4


Anatomical context of Bhlhb4

  • Here we demonstrate that the burst of IL-4 mRNA, peaking in draining lymph nodes of BALB/c mice 16 hr after infection, occurs within CD4+ T cells that express V beta 4 V alpha 8 T cell receptors [8].
  • Consistent with breakdown of the dentate filter, beta4 knockouts show distinctive seizures emanating from the temporal cortex, demonstrating a unique nonsynaptic mechanism for gate control of hippocampal synchronization leading to temporal lobe epilepsy [10].
  • In Purkinje cells, the only known sodium channel-associated subunit that has a cytoplasmic sequence with several positive charges and clustered hydrophobic/aromatic residues is beta4 (KKLITFILKKTREK; beta4(154-167)) [11].
  • The conclusion that "thymosin" beta 4 does not originate solely in the thymus gland is supported by the high concentrations found in tissues of athymic (nu/nu) mice [13].
  • Antisera that recognize the alpha 6 and beta 4 subunits of integrins were found by immunoelectron microscopy to localize to hemidesmosomes in the basal cells of mouse corneal epithelium [14].

Associations of Bhlhb4 with chemical compounds

  • Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis [2].
  • Another population (type B) of cells with large soma did not contain alpha3 and beta4 mRNAs but, systematically, alpha6 and beta3 (and often alpha4) and responded to nicotinic agonists in the order of nicotine > cytisine [15].
  • The alpha6beta4 integrin-a laminin-5 receptor-mediates assembly of hemidesmosomes and recruitment of Shc and phosphoinositide 3-kinase through the unique cytoplasmic extension of beta4 [16].
  • Type 3 nAChRs bind epibatidine with high affinity in equilibrium binding experiments and show that cytisine is as effective as nicotine in electrophysiological experiments; their distribution and persistence in beta2 -/- mice strongly suggest a subunit composition of alpha3 beta4 [17].
  • In mammals, beta4-GT has been recruited for a second biosynthetic function, the production of lactose which occurs exclusively in the lactating mammary gland [18].

Physical interactions of Bhlhb4

  • Interestingly, the Sp- and Sox10-binding sites on the beta4 promoter are located immediately adjacent to each other, raising the possibility that the two sets of factors functionally interact to regulate receptor gene expression [19].

Enzymatic interactions of Bhlhb4

  • Enhanced expression of Ca2+ channel alpha1A and beta4 subunits and phosphorylated tyrosine hydroxylase in the adrenal gland of N-type Ca2+ channel alpha1B subunit-deficient mice with a CBA/JN genetic background [20].
  • The mouse mutant lethargic (lh) exhibits severe neurological defects due to a mutation that deletes the alpha1 subunit interaction domain of the beta4 subunit [21].

Regulatory relationships of Bhlhb4

  • Cell culture studies showed that astrocyte expression of the beta4 and alpha5 integrins was significantly upregulated by IL-6 and IFN-alpha, respectively, while endothelial expression of these integrins was unchanged [22].
  • Expression of the beta 4 integrin subunit induces monocytic differentiation of 32D/v-Abl cells [23].
  • These findings provide evidence that beta4 signaling promotes epidermal growth and wound healing through a previously unrecognized effect on nuclear translocation of NF-kappaB and mitogen-activated protein kinases [16].
  • In this report, we demonstrate that neither full-length nor truncated beta4 protein is expressed in lh/lh mice [24].
  • We conclude that several properties of alpha1A and alpha1B proteins are not uniquely regulated by beta4 in vivo and may be rescued by beta1-3 subunit reshuffling [21].

Other interactions of Bhlhb4

  • We find that RAR beta 1/beta 3 promoter activity, which is apparently confined to the embryonic CNS, is not modified by RA treatment, unlike that of the RAR beta 2/beta 4 promoter (Mendelsohn et al., 1991) [25].
  • Two reports in this issue of Neuron reveal two transcription factors (Foxn4 and Bhlhb4) that contribute to the development of this remarkable cellular diversity [26].
  • Keratinocytes from beta4 mutant mice undergo extensive spreading but fail to proliferate and migrate in response to epidermal growth factor (EGF) on laminin-5 [16].
  • We have generated a conditional knockout mouse strain, in which the gene encoding the beta4 integrin subunit (Itgb4) was inactivated only in small stretches of the skin [27].
  • Since beta subunits regulate critical alpha1 subunit properties in heterologous expression systems, loss of beta4 in lethargic could dramatically alter channel localization and behavior unless beta1-3 subunits can be used as substitutes in vivo [21].

Analytical, diagnostic and therapeutic context of Bhlhb4


  1. The transcription factor Bhlhb4 is required for rod bipolar cell maturation. Bramblett, D.E., Pennesi, M.E., Wu, S.M., Tsai, M.J. Neuron (2004) [Pubmed]
  2. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Guo, W., Pylayeva, Y., Pepe, A., Yoshioka, T., Muller, W.J., Inghirami, G., Giancotti, F.G. Cell (2006) [Pubmed]
  3. Protein kinase Cdelta-mediated phosphorylation of alpha6beta4 is associated with reduced integrin localization to the hemidesmosome and decreased keratinocyte attachment. Alt, A., Ohba, M., Li, L., Gartsbein, M., Belanger, A., Denning, M.F., Kuroki, T., Yuspa, S.H., Tennenbaum, T. Cancer Res. (2001) [Pubmed]
  4. Retinal neuron activity of ETS domain-binding sites in a nicotinic acetylcholine receptor gene cluster enhancer. Francis, N., Deneris, E.S. J. Biol. Chem. (2002) [Pubmed]
  5. Suprabasal alpha6beta4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFbeta signalling. Owens, D.M., Romero, M.R., Gardner, C., Watt, F.M. J. Cell. Sci. (2003) [Pubmed]
  6. Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. van der Neut, R., Krimpenfort, P., Calafat, J., Niessen, C.M., Sonnenberg, A. Nat. Genet. (1996) [Pubmed]
  7. TH1 and TH2 cell antigen receptors in experimental leishmaniasis. Reiner, S.L., Wang, Z.E., Hatam, F., Scott, P., Locksley, R.M. Science (1993) [Pubmed]
  8. IL-4 rapidly produced by V beta 4 V alpha 8 CD4+ T cells instructs Th2 development and susceptibility to Leishmania major in BALB/c mice. Launois, P., Maillard, I., Pingel, S., Swihart, K.G., Xénarios, I., Acha-Orbea, H., Diggelmann, H., Locksley, R.M., MacDonald, H.R., Louis, J.A. Immunity (1997) [Pubmed]
  9. BHLHB4 is a bHLH transcriptional regulator in pancreas and brain that marks the dimesencephalic boundary. Bramblett, D.E., Copeland, N.G., Jenkins, N.A., Tsai, M.J. Genomics (2002) [Pubmed]
  10. BK channel beta4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Brenner, R., Chen, Q.H., Vilaythong, A., Toney, G.M., Noebels, J.L., Aldrich, R.W. Nat. Neurosci. (2005) [Pubmed]
  11. Open-channel block by the cytoplasmic tail of sodium channel beta4 as a mechanism for resurgent sodium current. Grieco, T.M., Malhotra, J.D., Chen, C., Isom, L.L., Raman, I.M. Neuron (2005) [Pubmed]
  12. Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. Dowling, J., Yu, Q.C., Fuchs, E. J. Cell Biol. (1996) [Pubmed]
  13. Thymosin beta 4: a ubiquitous peptide in rat and mouse tissues. Hannappel, E., Xu, G.J., Morgan, J., Hempstead, J., Horecker, B.L. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  14. Alpha 6 beta 4 integrin heterodimer is a component of hemidesmosomes. Stepp, M.A., Spurr-Michaud, S., Tisdale, A., Elwell, J., Gipson, I.K. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  15. Diversity and distribution of nicotinic acetylcholine receptors in the locus ceruleus neurons. Léna, C., de Kerchove D'Exaerde, A., Cordero-Erausquin, M., Le Novère, N., del Mar Arroyo-Jimenez, M., Changeux, J.P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  16. Targeted deletion of the integrin beta4 signaling domain suppresses laminin-5-dependent nuclear entry of mitogen-activated protein kinases and NF-kappaB, causing defects in epidermal growth and migration. Nikolopoulos, S.N., Blaikie, P., Yoshioka, T., Guo, W., Puri, C., Tacchetti, C., Giancotti, F.G. Mol. Cell. Biol. (2005) [Pubmed]
  17. Identification of four classes of brain nicotinic receptors using beta2 mutant mice. Zoli, M., Léna, C., Picciotto, M.R., Changeux, J.P. J. Neurosci. (1998) [Pubmed]
  18. Transcriptional regulation of murine beta1,4-galactosyltransferase in somatic cells. Analysis of a gene that serves both a housekeeping and a mammary gland-specific function. Rajput, B., Shaper, N.L., Shaper, J.H. J. Biol. Chem. (1996) [Pubmed]
  19. Synergistic transcriptional activation by Sox10 and Sp1 family members. Melnikova, I.N., Lin, H.R., Blanchette, A.R., Gardner, P.D. Neuropharmacology (2000) [Pubmed]
  20. Enhanced expression of Ca2+ channel alpha1A and beta4 subunits and phosphorylated tyrosine hydroxylase in the adrenal gland of N-type Ca2+ channel alpha1B subunit-deficient mice with a CBA/JN genetic background. Takahashi, E., Nagasu, T. Comp. Med. (2006) [Pubmed]
  21. beta subunit reshuffling modifies N- and P/Q-type Ca2+ channel subunit compositions in lethargic mouse brain. Burgess, D.L., Biddlecome, G.H., McDonough, S.I., Diaz, M.E., Zilinski, C.A., Bean, B.P., Campbell, K.P., Noebels, J.L. Mol. Cell. Neurosci. (1999) [Pubmed]
  22. Increased expression of the beta4 and alpha5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-alpha in the central nervous system. Milner, R., Campbell, I.L. Mol. Cell. Neurosci. (2006) [Pubmed]
  23. Expression of the beta 4 integrin subunit induces monocytic differentiation of 32D/v-Abl cells. Morena, A., Riccioni, S., Marchetti, A., Polcini, A.T., Mercurio, A.M., Blandino, G., Sacchi, A., Falcioni, R. Blood (2002) [Pubmed]
  24. Altered expression and assembly of N-type calcium channel alpha1B and beta subunits in epileptic lethargic (lh/lh) mouse. McEnery, M.W., Copeland, T.D., Vance, C.L. J. Biol. Chem. (1998) [Pubmed]
  25. RAR beta isoforms: distinct transcriptional control by retinoic acid and specific spatial patterns of promoter activity during mouse embryonic development. Mendelsohn, C., Larkin, S., Mark, M., LeMeur, M., Clifford, J., Zelent, A., Chambon, P. Mech. Dev. (1994) [Pubmed]
  26. Out-foxing fate; molecular switches create neuronal diversity in the retina. Kay, J.N., Baier, H. Neuron (2004) [Pubmed]
  27. Keratinocytes display normal proliferation, survival and differentiation in conditional beta4-integrin knockout mice. Raymond, K., Kreft, M., Janssen, H., Calafat, J., Sonnenberg, A. J. Cell. Sci. (2005) [Pubmed]
  28. The beta 4 subunit of the integrin family is displayed on a restricted subset of endothelium in mice. Kennel, S.J., Godfrey, V., Ch'ang, L.Y., Lankford, T.K., Foote, L.J., Makkinje, A. J. Cell. Sci. (1992) [Pubmed]
  29. Redistribution of the hemidesmosome components alpha 6 beta 4 integrin and bullous pemphigoid antigens during epithelial wound healing. Gipson, I.K., Spurr-Michaud, S., Tisdale, A., Elwell, J., Stepp, M.A. Exp. Cell Res. (1993) [Pubmed]
  30. Calcium channel subunits in the mouse cochlea. Green, G.E., Khan, K.M., Beisel, D.W., Drescher, M.J., Hatfield, J.S., Drescher, D.G. J. Neurochem. (1996) [Pubmed]
  31. Mouse strain-specific nicotinic acetylcholine receptor expression by inhibitory interneurons and astrocytes in the dorsal hippocampus. Gahring, L.C., Persiyanov, K., Dunn, D., Weiss, R., Meyer, E.L., Rogers, S.W. J. Comp. Neurol. (2004) [Pubmed]
  32. Molecular cloning and expression of mouse mg(2+)-dependent protein phosphatase beta-4 (type 2C beta-4). Kato, S., Terasawa, T., Kobayashi, T., Ohnishi, M., Sasahara, Y., Kusuda, K., Yanagawa, Y., Hiraga, A., Matsui, Y., Tamura, S. Arch. Biochem. Biophys. (1995) [Pubmed]
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