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Myocyte enhancer factor-2 transcription factors in neuronal differentiation and survival

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Abstract

Myocyte enhancer factor-2 (MEF2) transcription factors regulate genes that control critical cellular processes including proliferation, differentiation, and survival. Although MEF2 proteins were first identified as transcription factors that bound A/T rich DNA sequences and controlled muscle-specific genes during myogenic development, it is now apparent that MEF2 transcription factors are also highly expressed in neurons and are critical determinants of neuronal differentiation and fate. Here we focus our discussion on the role of MEF2 proteins in nervous tissue and the regulation of these transcription factors by calcium and phosphorylation signaling pathways.

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References

  1. Yu Y.T., Breitbart R.E., Smoot L.B., Lee Y., Mahdavi V., Nadal-Ginard B. (1992) Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MADS box transcription factors. Genes Dev. 6, 1783–1798.

    Article  PubMed  CAS  Google Scholar 

  2. Naya F.S., Olson E. (1999) MEF2: a transcriptional target for signaling pathways controlling skeletal muscle growth and differentiation. Curr. Opin. Cell Biol. 11, 683–688.

    Article  PubMed  CAS  Google Scholar 

  3. Shore P., Sharrocks A.D. (1995) The MADS-box family of transcription factors. Eur. J. Biochem. 229, 1–13.

    Article  PubMed  CAS  Google Scholar 

  4. Breitbart R.E., Liang C.S., Smoot L.B., Laheru D.A., Mahdavi V., Nadal-Ginard B. (1993) A fourth human MEF2 transcription factor, hMEF2D, is an early marker of the myogenic lineage. Development 118, 1095–1106.

    PubMed  CAS  Google Scholar 

  5. Leifer D., Krainc D., Yu Y.T., et al. (1993) MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex. Proc. Natl. Acad. Sci. USA 90, 1546–1550.

    Article  PubMed  CAS  Google Scholar 

  6. McDermott J.C., Cardoso M.C., Yu Y.T., et al. (1993) hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors. Mol. Cell. Biol. 13, 2564–2577.

    PubMed  CAS  Google Scholar 

  7. Martin J.F., Miano J.M., Hustad C.M., Copeland N.G., Jenkins N.A., Olson E.N. (1994) A Mef2 gene that generates a muscle-specific isoform via alternative mRNA splicing. Mol. Cell. Biol. 14, 1647–1656.

    PubMed  CAS  Google Scholar 

  8. Moore S., Vrebalov J., Payton P., Giovannoni J. (2002) Use of genomics tools to isolate key ripening genes and analyse fruit maturation in tomato. J. Exp. Bot. 53, 2023–2030.

    Article  PubMed  CAS  Google Scholar 

  9. Ng M., Yanofsky M.F. (2001) Function and evolution of the plant MADS-box gene family. Nat. Rev. Genet. 2, 186–195.

    Article  PubMed  CAS  Google Scholar 

  10. Yun K., Wold B. (1996) Skeletal muscle determination and differentiation: story of a core regulatory network and its context. Curr. Opin. Cell Biol. 8, 877–889.

    Article  PubMed  CAS  Google Scholar 

  11. Black B.L., Olson E.N. (1998) Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu. Rev. Cell. Dev. Biol. 14, 167–196.

    Article  PubMed  CAS  Google Scholar 

  12. McKinsey T.A., Zhang C.L., Olson E.N. (2002) MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem. Sci. 27, 40–47.

    Article  PubMed  CAS  Google Scholar 

  13. Molkentin J.D., Firulli A.B., Black B.L., et al. (1996) MEF2B is a potent transactivator expressed in early myogenic lineages. Mol. Cell. Biol. 16, 3814–3824.

    PubMed  CAS  Google Scholar 

  14. Molkentin J.D., Olson E.N. (1996) Combinatorial control of muscle development by basic helix-loop-helix and MADS-box transcription factors. Proc. Natl. Acad. Sci. USA 93, 9366–9373.

    Article  PubMed  CAS  Google Scholar 

  15. Ornatsky O.I., McDermott J.C. (1996) MEF2 protein expression, DNA binding specificity and complex composition, and transcriptional activity in muscle and non-muscle cells. J. Biol. Chem. 271, 24927–24933.

    Article  PubMed  CAS  Google Scholar 

  16. Puri P.L., Sartorelli V. (2000) Regulation of muscle regulatory factors by DNA-binding, interacting proteins, and post-transcriptional modifications. J. Cell. Physiol. 185, 155–173.

    Article  PubMed  CAS  Google Scholar 

  17. Puri P.L., Wu Z., Zhang P., et al. (2000) Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells. Genes Dev. 14, 574–584.

    PubMed  CAS  Google Scholar 

  18. Lin Q., Schwarz J., Bucana C., Olson E.N. (1997) Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276, 1404–1407.

    Article  PubMed  CAS  Google Scholar 

  19. Bour B.A., O’Brien M.A., Lockwood W.L., et al. (1995) Drosophila MEF2, a transcription factor that is essential for myogenesis. Genes Dev. 9, 730–741.

    Article  PubMed  CAS  Google Scholar 

  20. Prokop A., Landgraf M., Rushton E., Broadie K., Bate M. (1996) Presynaptic development at the Drosophila neuromuscular junction: assembly and localization of presynaptic active zones. Neuron 17, 617–626.

    Article  PubMed  CAS  Google Scholar 

  21. Kolodziejczyk S.M., Wang L., Balazsi K., DeRepentigny Y., Kothary R., Megeney L.A. (1999) MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium. Curr. Biol. 9, 1203–1206.

    Article  PubMed  CAS  Google Scholar 

  22. Passier R., Zeng H., Frey N., et al. (2000) CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J. Clin. Invest. 105, 1395–1406.

    Article  PubMed  CAS  Google Scholar 

  23. Zhang C.L., McKinsey T.A., Chang S., Antos C.L., Hill J.A., Olson E.N. (2002) Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488.

    Article  PubMed  CAS  Google Scholar 

  24. Youn H.D., Sun L., Prywes R., Liu J.O. (1999) Apoptosis of T cells mediated by Ca2+-induced release of the transcription factor MEF2. Science 286, 790–793.

    Article  PubMed  CAS  Google Scholar 

  25. Youn H.D., Chatila T.A., Liu J.O. (2000) Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. Embo J. 19, 4323–4331.

    Article  PubMed  CAS  Google Scholar 

  26. Leifer D., Golden J., Kowall N.W. (1994) Myocyte-specific enhancer binding factor 2C expression in human brain development. Neuroscience 63, 1067–1079.

    Article  PubMed  CAS  Google Scholar 

  27. Lyons G.E., Micales B.K., Schwarz J., Martin J.F., Olson E.N. (1995) Expression of mef2 genes in the mouse central nervous system suggests a role in neuronal maturation. J. Neurosci. 15, 5727–5738.

    PubMed  CAS  Google Scholar 

  28. Ikeshima H., Imai S., Shimoda K., Hata J., Takano T. (1995) Expression of a MADS box gene, MEF2D, in neurons of the mouse central nervous system: implication of its binary function in myogenic and neurogenic cell lineages. Neurosci. Lett. 200, 117–120.

    Article  PubMed  CAS  Google Scholar 

  29. Mao Z., Wiedmann M. (1999) Calcineurin enhances MEF2 DNA binding activity in calcium-dependent survival of cerebellar granule neurons. J. Biol. Chem. 274, 31102–31107.

    Article  PubMed  CAS  Google Scholar 

  30. Lin X., Shah S., Bulleit R.F. (1996) The expression of MEF2 genes is implicated in CNS neuronal differentiation. Brain Res. Mol. Brain Res. 42, 307–316.

    Article  PubMed  CAS  Google Scholar 

  31. Mao Z., Bonni A., Xia F., Nadal-Vicens M., Greenberg M.E. (1999) Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286, 785–790.

    Article  PubMed  CAS  Google Scholar 

  32. Li M., Linseman D.A., Allen M.P., et al. (2001) Myocyte enhancer factor 2A and 2D undergo phosphorylation and caspase-mediated degradation during apoptosis of rat cerebellar granule neurons. J. Neurosci. 21, 6544–6552.

    PubMed  CAS  Google Scholar 

  33. Gaudilliere B., Shi Y., Bonni A. (2002) RNA interference reveals a requirement for myocyte enhancer factor 2A in activity-dependent neuronal survival. J. Biol. Chem. 277, 46442–46446.

    Article  PubMed  CAS  Google Scholar 

  34. Okamoto S., Li Z., Ju C., Scholzke M.N., Mathews E., et al. (2002) Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis. Proc. Natl. Acad. Sci. USA 99, 3974–3979.

    Article  PubMed  CAS  Google Scholar 

  35. Okamoto S., Krainc D., Sherman K., Lipton S.A. (2000) Antiapoptotic role of the p38 mitogen-activated protein kinase-myocyte enhancer factor 2 transcription factor pathway during neuronal differentiation. Proc. Natl. Acad. Sci. USA 97, 7561–7566.

    Article  PubMed  CAS  Google Scholar 

  36. Skerjanc I.S., Wilton S. (2000) Myocyte enhancer factor 2C upregulates MASH-1 expression and induces neurogenesis in P19 cells. FEBS Lett. 472, 53–56.

    Article  PubMed  CAS  Google Scholar 

  37. Krainc D., Bai G., Okamoto S., et al. (1998) Synergistic activation of the N-methyl-D-aspartate receptor subunit 1 promoter by myocyte enhancer factor 2C and Sp1. J. Biol. Chem. 273, 26218–26224.

    Article  PubMed  CAS  Google Scholar 

  38. Allen M.P., Xu M., Linseman D.A., et al. (2002) Adhesion-related kinase repression of gonadotropin-releasing hormone gene expression requires Rac activation of the extracellular signal-regulated kinase pathway. J. Biol. Chem. 277, 38133–38140.

    Article  PubMed  CAS  Google Scholar 

  39. Molkentin J.D., Li L., Olson E.N. (1996) Phosphorylation of the MADS-Box transcription factor MEF2C enhances its DNA binding activity. J. Biol. Chem. 271, 17199–17204.

    Article  PubMed  CAS  Google Scholar 

  40. Yang S.H., Galanis A., Sharrocks A.D. (1999) Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors. Mol. Cell. Biol. 19, 4028–4038.

    PubMed  CAS  Google Scholar 

  41. Zhao M., New L., Kravchenko V.V., et al. (1999) Regulation of the MEF2 family of transcription factors by p38. Mol. Cell. Biol. 19, 21–30.

    PubMed  CAS  Google Scholar 

  42. Wu Z., Woodring P.J., Bhakta K.S., et al. (2000) p38 and extracellular signal-regulated kinases regulate the myogenic program at multiple steps. Mol. Cell. Biol. 20, 3951–3964.

    Article  PubMed  CAS  Google Scholar 

  43. Ornatsky O.I., Cox D.M., Tangirala P., et al. (1999) Post-translational control of the MEF2A transcriptional regulatory protein. Nucleic Acids Res. 27, 2646–2654.

    Article  PubMed  CAS  Google Scholar 

  44. Han J., Jiang Y., Li Z., Kravchenko V.V., Ulevitch R.J. (1997) Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature 386, 296–299.

    Article  PubMed  CAS  Google Scholar 

  45. Wu H., Naya F.J., McKinsey T.A., et al. (2000) MEF2 responds to multiple calcium-regulated signals in the control of skeletal muscle fiber type. Embo J. 19, 1963–1973.

    Article  PubMed  CAS  Google Scholar 

  46. Kato Y., Kravchenko V.V., Tapping R.I., Han J., Ulevitch R.J., Lee J.D. (1997) BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. Embo J. 16, 7054–7066.

    Article  PubMed  CAS  Google Scholar 

  47. Yang C.C., Ornatsky O.I., McDermott J.C., Cruz T.F., Prody C.A. (1998) Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1. Nucleic Acids Res. 26, 4771–4777.

    Article  PubMed  CAS  Google Scholar 

  48. Kato Y., Zhao M., Morikawa A., et al. (2000) Big mitogen-activated kinase regulates multiple members of the MEF2 protein family. J. Biol. Chem. 275, 18534–18540.

    Article  PubMed  CAS  Google Scholar 

  49. Marinissen M.J., Chiariello M., Pallante M., Gutkind J.S. (1999) A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: a role for c-Jun NH2-terminal kinase, p38s, and extracellular signal-regulated kinase 5. Mol. Cell. Biol. 19, 4289–4301.

    PubMed  CAS  Google Scholar 

  50. Kasler H.G., Victoria J., Duramad O., Winoto A. (2000) ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Mol. Cell. Biol. 20, 8382–8389.

    Article  PubMed  CAS  Google Scholar 

  51. Liu L., Cavanaugh J.E., Wang Y., Sakagami H., Mao Z., Xia Z. (2003) ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons. Proc. Natl. Acad. Sci. USA 100, 8532–8537.

    Article  PubMed  CAS  Google Scholar 

  52. Shalizi A., Lehtinen M., Gaudilliere B., et al. (2003) Characterization of a neurotrophin signaling mechanism that mediates neuron survival in a temporally specific pattern. J. Neurosci. 23, 7326–7336.

    PubMed  CAS  Google Scholar 

  53. Linseman D.A., Cornejo B.J., Le S.S., et al. (2003) A myocyte enhancer factor 2D (MEF2D) kinase activated during neuronal apoptosis is a novel target inhibited by lithium. J. Neurochem. 85, 1488–1499.

    Article  PubMed  CAS  Google Scholar 

  54. Gong X., X. T, Wiedmann M, Wang X, et al. (2003) Cdk-5 mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron 38, 33–46.

    Article  PubMed  CAS  Google Scholar 

  55. Grant P., Sharma P., Pant H.C. (2001) Cyclin-dependent protein kinase 5 (Cdk5) and the regulation of neurofilament metabolism. Eur. J. Biochem. 268, 1534–1546.

    Article  PubMed  CAS  Google Scholar 

  56. Bajaj N.P. (2000) Cyclin-dependent kinase-5 (CDK5) and amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 1, 319–327.

    Article  PubMed  CAS  Google Scholar 

  57. Maccioni R.B., Otth C., Concha I.I., Munoz J.P. (2001) The protein kinase Cdk5. Structural aspects, roles in neurogenesis and involvement in Alzheimer’s pathology. Eur. J. Biochem. 268, 1518–1527.

    Article  PubMed  CAS  Google Scholar 

  58. Takahashi M., Iseki E., Kosaka K. (2000) Cyclin-dependent kinase 5 (Cdk5) associated with Lewy bodies in diffuse Lewy body disease. Brain Res. 862, 253–256.

    Article  PubMed  CAS  Google Scholar 

  59. Lu J., McKinsey T.A., Zhang C.L., Olson E.N. (2000) Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases. Mol. Cell 6, 233–244.

    Article  PubMed  CAS  Google Scholar 

  60. McKinsey T.A., Zhang C.L., Lu J., Olson E.N. (2000) Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408, 106–111.

    Article  PubMed  CAS  Google Scholar 

  61. Kao H.Y., Verdel A., Tsai C.C., Simon C., Juguilon H., Khochbin S. (2001) Mechanism for nucleocytoplasmic shuttling of histone deacetylase 7. J. Biol. Chem. 276, 47496–47507.

    Article  PubMed  CAS  Google Scholar 

  62. Zhang C.L., McKinsey T.A., Olson E.N. (2001) The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc. Natl. Acad. Sci. USA 98, 7354–7359.

    Article  PubMed  CAS  Google Scholar 

  63. Linseman P.A., Bartley C.M., Le S.S., et al. (2003). Inactivation of the myocyte enhancer factor-2 repressor histone deacetylase-5 by endogenous Ca(2+)/calmodulin-dependent kinase II promotes depolarization-mediated cerebellar granule neuron survival. J. Biol. Chem. 278, 41472–41481.

    Article  PubMed  CAS  Google Scholar 

  64. Chawla S., Vanhoutte P., Arnold F.J., Huang C.L., Bading H. (2003) Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J. Neurochem. 85, 151–159.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology, University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center, 80262, Denver, Colorado

    Kim A. Heidenreich & Daniel A. Linseman

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  1. Kim A. Heidenreich
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Heidenreich, K.A., Linseman, D.A. Myocyte enhancer factor-2 transcription factors in neuronal differentiation and survival. Mol Neurobiol 29, 155–165 (2004). https://doi.org/10.1385/MN:29:2:155

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