Not Just for Muscle Anymore: Activity and Calcium Regulation of MEF2-Dependent Transcription in Neuronal Survival and Differentiation

  • Aryaman Shalizi
  • Azad Bonni


Post-mitotic neurons of the central nervous system express one or more MEF2 proteins from the time of cell-cycle exit through adulthood. Furthermore, it is now evident that MEF2 regulates diverse aspects of neuronal development including cell survival and synaptogenesis. MEF2 proteins are bifunctional transcriptional regulators, a property that arises from the signal-dependent association of MEF2 proteins with distinct chromatin modifying activities. The goal of this chapter is to provide an account of the various control mechanisms that MEF2 proteins are subjected to within the central nervous system, placing a specific emphasis on the contribution of activity- and calcium-dependent signaling pathways.


Cerebellar Granule Neuron Dendritic Morphogenesis Internal Granule Layer MEF2C Gene Transcription Factor MEF2C 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Altman, J. and Bayer, S. A. (1997) Development of the cerebellar system: in relation to its evolution, structure, and functions. CRC Press, Boca Raton.Google Scholar
  2. Andres, V., Cervera, M. and Mahdavi, V. (1995) Determination of the consensus binding site for MEF2 expressed in muscle and brain reveals tissue-specific sequence constraints. J. Biol. Chem. 270, 23246–23249.PubMedCrossRefGoogle Scholar
  3. Aramburu, J., Rao, A. and Klee, C. B. (2000) Calcineurin: from structure to function. Curr. Top. Cell Regul. 36, 237–295.PubMedCrossRefGoogle Scholar
  4. Arnold, H. H. and Winter, B. (1998) Muscle differentiation: more complexity to the network of myogenic regulators. Curr. Opin. Genet. Dev. 8, 539–544.PubMedCrossRefGoogle Scholar
  5. Barsyte-Lovejoy, D., Galanis, A., Clancy, A. and Sharrocks, A. D. (2004) ERK5 is targeted to myocyte enhancer factor 2A (MEF2A) through a MAPK docking motif. Biochem. J. 381, 693–699.PubMedCrossRefGoogle Scholar
  6. Belfield, J. L., Whittaker, C., Cader, M. Z. and Chawla, S. (2006) Differential effects of Ca2+ and cAMP on transcription mediated by MEF2D and cAMP-response element-binding protein in hippocampal neurons. J. Biol. Chem. 281, 27724–27732.PubMedCrossRefGoogle Scholar
  7. Benedito, A. B., Lehtinen, M., Massol, R., Lopes, U. G., Kirchhausen, T., Rao, A. and Bonni, A. (2005) The transcription factor NFAT3 mediates neuronal survival. J. Biol. Chem. 280, 2818–2825.Google Scholar
  8. Black, B. L., Ligon, K. L., Zhang, Y. and Olson, E. N. (1996) Cooperative transcriptional activation by the neurogenic basic helix-loop-helix protein MASH1 and members of the myocyte enhancer factor-2 (MEF2) family. J. Biol. Chem. 271, 26659–26663.PubMedCrossRefGoogle Scholar
  9. Black, B. L. and Olson, E. N. (1998) Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu. Rev. Cell Dev. Biol. 14, 167–196.PubMedCrossRefGoogle Scholar
  10. Bonhoeffer, T. and Yuste, R. (2002) Spine motility. Phenomenology, mechanisms, and function. Neuron 35, 1019–1027.Google Scholar
  11. Buonanno, A. and Fields, R. D. (1999) Gene regulation by patterned electrical activity during neural and skeletal muscle development. Curr. Opin. in Neurobio. 9, 110–120.CrossRefGoogle Scholar
  12. Butts, B. D., Linseman, D. A., Le, S. S., Laessig, T. A. and Heidenreich, K. A. (2003) Insulin-like growth factor-I suppresses degradation of the pro-survival transcription factor myocyte enhancer factor 2D (MEF2D) during neuronal apoptosis. Horm. Metab. Res. 35(11–12), 763–770.Google Scholar
  13. Cavanaugh, J. E. (2004) Role of extracellular signal regulated kinase 5 in neuronal survival. Eur. J. Biochem. 271, 2056–2059.PubMedCrossRefGoogle Scholar
  14. Cavanaugh, J. E., Ham, J., Hetman, M., Poser, S., Yan, C. and Xia, Z. (2001) Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J. Neurosci. 21, 434–443.PubMedGoogle Scholar
  15. Chang, S. H., Poser, S. and Xia, Z. (2004) A novel role for serum response factor in neuronal survival. J. Neurosci. 24, 2277–2285.PubMedCrossRefGoogle Scholar
  16. Chawla, S., Vanhoutte, P., Arnold, F. J., Huang, C. L. and Bading, H. (2003) Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J. Neurochem. 85, 151–159.PubMedCrossRefGoogle Scholar
  17. Cheung, Z. H., Fu, A. K. and Ip, N. Y. (2006) Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases. Neuron 50, 13–18.PubMedCrossRefGoogle Scholar
  18. Chin, E. R., Olson, E. N., Richardson, J. A., Yang, Q., Humphries, C., Shelton, J. M., Wu, H., Zhu, W., Bassel-Duby, R. and Williams, R. S. (1998) A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev. 12, 2499–2509.PubMedGoogle Scholar
  19. Chklovskii, D. B., Mel, B. W. and Svoboda, K. (2004) Cortical rewiring and information storage. Nature 431, 782–788.PubMedCrossRefGoogle Scholar
  20. Chupreta, S., Holmstrom, S., Subramanian, L. and Iniguez-Lluhi, J. A. (2005) A small conserved surface in SUMO is the critical structural determinant of its transcriptional inhibitory properties. Mol. Cell. Biol. 25, 4272–4282.Google Scholar
  21. Cox, D. M., Du, M., Marback, M., Yang, E. C., Chan, J., Siu, K. W. and McDermott, J. C. (2003) Phosphorylation motifs regulating the stability and function of myocyte enhancer factor 2A. J. Biol. Chem. 278, 15297–15303.Google Scholar
  22. Cripps, R. M., Black, B. L., Zhao, B., Lien, C. L., Schulz, R. A. and Olson, E. N. (1998) The myogenic regulatory gene MEF2 is a direct target for transcriptional activation by Twist during Drosophila myogenesis. Genes Dev. 12, 422–434.PubMedGoogle Scholar
  23. Cruz, J. C., Tseng, H. C., Goldman, J. A., Shih, H. and Tsai, L. H. (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471–483.PubMedCrossRefGoogle Scholar
  24. Dhavan, R. and Tsai, L. H. (2001) A decade of CDK5. Nat. Rev. Mol. Cell Biol. 2, 749–759.PubMedCrossRefGoogle Scholar
  25. Dichoso, D., Brodigan, T., Chwoe, K. Y., Lee, J. S., Llacer, R., Park, M., Corsi, A. K., Kostas, S. A., Fire, A., Ahnn, J. and Krause, M. (2000) The MADS-Box factor CeMEF2 is not essential for Caenorhabditis elegans myogenesis and development. Dev. Biol. 223, 431–440.PubMedCrossRefGoogle Scholar
  26. Dodou, E., Sparrow, D. B., Mohun, T. and Treisman, R. (1995) MEF2 proteins, including MEF2A, are expressed in both muscle and non-muscle cells. Nucleic Acids Res. 23, 4267–4274.PubMedCrossRefGoogle Scholar
  27. Dodou, E., Xu, S. M. and Black, B. L. (2003) MEF2c is activated directly by myogenic basic helix-loop-helix proteins during skeletal muscle development in vivo. Mech. Dev. 120, 1021–1032.PubMedCrossRefGoogle Scholar
  28. Finkbeiner, S. and Greenberg, M. E. (1996) Ca(2+)-dependent routes to Ras: mechanisms for neuronal survival, differentiation, and plasticity? Neuron 16, 233–236.Google Scholar
  29. Fischle, W., Dequiedt, F., Hendzel, M. J., Guenther, M. G., Lazar, M. A., Voelter, W. and Verdin, E. (2002) Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol. Cell 9, 45–57.PubMedCrossRefGoogle Scholar
  30. Flavell, S. W., Cowan, C. W., Kim, T. K., Greer, P. L., Lin, Y., Paradis, S., Griffith, E. C., Hu, L. S., Chen, C. and Greenberg, M. E. (2006) Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008–1012.PubMedCrossRefGoogle Scholar
  31. Gaudilliere, B., Shi, Y. and Bonni, A. (2002) RNA interference reveals a requirement for myocyte enhancer factor 2A in activity-dependent neuronal survival. J. Biol. Chem. 277, 46442–46446.PubMedCrossRefGoogle Scholar
  32. Ghosh, A. and Greenberg, M. E. (1995) Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science 268, 239–247.PubMedCrossRefGoogle Scholar
  33. Gill, G. (2003) Post-translational modification by the small ubiquitin-related modifier SUMO has big effects on transcription factor activity. Curr. Opin. Genet. Dev. 13, 108–113.PubMedCrossRefGoogle Scholar
  34. Gong, X., Tang, X., Wiedmann, M., Wang, X., Peng, J., Zheng, D., Blair, L. A., Marshall, J. and Mao, Z. (2003) Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron 38, 33–46.PubMedCrossRefGoogle Scholar
  35. Gregoire, S., Tremblay, A. M., Xiao, L., Yang, Q., Ma, K., Nie, J., Mao, Z., Wu, Z., Giguere, V. and Yang, X. J. (2006) Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation. J. Biol. Chem. 281, 4423–4433.PubMedCrossRefGoogle Scholar
  36. Gregoire, S. and Yang, X. J. (2005) Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors. Mol. Cell. Biol. 25, 2273–2287.PubMedCrossRefGoogle Scholar
  37. Grozinger, C. M., Hassig, C. A. and Schreiber, S. L. (1999) Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc. Natl. Acad. Sci. USA. 96, 4868–4873.Google Scholar
  38. Grozinger, C. M. and Schreiber, S. L. (2000) Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc. Natl. Acad. Sci. USA. 97, 7835–7840.Google Scholar
  39. Gunthorpe, D., Beatty, K. E. and Taylor, M. V. (1999) Different levels, but not different isoforms, of the Drosophila transcription factor DMEF2 affect distinct aspects of muscle differentiation. Dev. Biol. 215, 130–145.PubMedCrossRefGoogle Scholar
  40. Han, J., Jiang, Y., Li, Z., Kravchenko, V. V. and Ulevitch, R. J. (1997) Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature 386, 296–299.PubMedCrossRefGoogle Scholar
  41. Heidenreich, K. A. and Linseman, D. A. (2004) Myocyte enhancer factor-2 transcription factors in neuronal differentiation and survival. Mol. Neurobiol. 29, 155–166.PubMedCrossRefGoogle Scholar
  42. Holmstrom, S., Van Antwerp, M. E. and Iniguez-Lluhi, J. A. (2003) Direct and distinguishable inhibitory roles for SUMO isoforms in the control of transcriptional synergy. Proc. Natl. Acad. Sci. USA. 100, 15758–15763.PubMedCrossRefGoogle Scholar
  43. Holtmaat, A. J., Trachtenberg, J. T., Wilbrecht, L., Shepherd, G. M., Zhang, X., Knott, G. W. and Svoboda, K. (2005) Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45, 279–291.PubMedCrossRefGoogle Scholar
  44. Ikeshima, H., Imai, S., Shimoda, K., Hata, J. and 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.PubMedCrossRefGoogle Scholar
  45. Iniguez-Lluhi, J. A. and Pearce, D. (2000) A common motif within the negative regulatory regions of multiple factors inhibits their transcriptional synergy. Mol. Cell. Biol. 20, 6040–6050.PubMedCrossRefGoogle Scholar
  46. Johnson, E. S. (2004) Protein modification by SUMO. Annu Rev Biochem 73, 355–382.PubMedCrossRefGoogle Scholar
  47. Kandel, E. R. (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038.PubMedCrossRefGoogle Scholar
  48. Kang, J., Gocke, C. B. and Yu, H. (2006) Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity. BMC biochemistry 7, 5.PubMedCrossRefGoogle Scholar
  49. Kato, Y., Kravchenko, V. V., Tapping, R. I., Han, J., Ulevitch, R. J. and Lee, J. D. (1997) BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J. 16, 7054–7066.PubMedCrossRefGoogle Scholar
  50. Kaushal, S., Schneider, J. W., Nadal-Ginard, B. and Mahdavi, V. (1994) Activation of the myogenic lineage by MEF2A, a factor that induces and cooperates with MyoD. Science 266, 1236–1240.PubMedCrossRefGoogle Scholar
  51. Knott, G. W., Holtmaat, A., Wilbrecht, L., Welker, E. and Svoboda, K. (2006) Spine growth precedes synapse formation in the adult neocortex in vivo. Nat. Neurosci. 9, 1117–1124.PubMedCrossRefGoogle Scholar
  52. Lee, M. S., Kwon, Y. T., Li, M., Peng, J., Friedlander, R. M. and Tsai, L. H. (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405, 360–364.PubMedCrossRefGoogle Scholar
  53. Leifer, D., Golden, J. and Kowall, N. W. (1994) Myocyte-specific enhancer binding factor 2C expression in human brain development. Neuroscience 63, 1067–1079.PubMedCrossRefGoogle Scholar
  54. Leifer, D., Krainc, D., Yu, Y. T., McDermott, J., Breitbart, R. E., Heng, J., Neve, R. L., Kosofsky, B., Nadal-Ginard, B. and Lipton, S. A. (1993) MEF2C, a MADS/MEF2-family transcription factor expressed in a laminar distribution in cerebral cortex. Proc. Natl. Acad. Sci. USA. 90, 1546–1550.PubMedCrossRefGoogle Scholar
  55. Lemercier, C., Verdel, A., Galloo, B., Curtet, S., Brocard, M. P. and Khochbin, S. (2000) mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity. J. Biol. Chem. 275, 15594–15599.PubMedCrossRefGoogle Scholar
  56. Li, M., Linseman, D. A., Allen, M. P., Meintzer, M. K., Wang, X., Laessig, T., Wierman, M. E. and Heidenreich, K. A. (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.PubMedGoogle Scholar
  57. Lin, X., Shah, S. and Bulleit, R. F. (1996) The expression of MEF2 genes is implicated in CNS neuronal differentiation. Brain Res. Mol. Brain Res. 42, 307–316.PubMedCrossRefGoogle Scholar
  58. Linseman, D. A., Bartley, C. M., Le, S. S., Laessig, T. A., Bouchard, R. J., Meintzer, M. K., Li, M. and Heidenreich, K. A. (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.PubMedCrossRefGoogle Scholar
  59. Linseman, D. A., Cornejo, B. J., Le, S. S., Meintzer, M. K., Laessig, T. A., Bouchard, R. J. and Heidenreich, K. A. (2003) A myocyte enhancer factor 2D (MEF2D) kinase activated during neuronal apoptosis is a novel target inhibited by lithium. J. Neurochem. 85, 1488–1499.PubMedCrossRefGoogle Scholar
  60. Lu, J., McKinsey, T. A., Nicol, R. L. and Olson, E. N. (2000) Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc. Natl. Acad. Sci. USA. 97, 4070–4075.PubMedCrossRefGoogle Scholar
  61. Lu, J., McKinsey, T. A., Zhang, C. L. and 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.PubMedCrossRefGoogle Scholar
  62. Luo, L. (2002) Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu. Rev. Cell Dev. Biol. 18, 601–635.PubMedCrossRefGoogle Scholar
  63. Lyons, G. E., Micales, B. K., Schwarz, J., Martin, J. F. and 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.PubMedGoogle Scholar
  64. Ma, K., Chan, J. K., Zhu, G. and Wu, Z. (2005) Myocyte enhancer factor 2 acetylation by p300 enhances its DNA binding activity, transcriptional activity, and myogenic differentiation. Mol. Cell. Biol. 25, 3575–3582.PubMedCrossRefGoogle Scholar
  65. Mao, Z., Bonni, A., Xia, F., Nadal-Vicens, M. and Greenberg, M. E. (1999) Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286, 785–790.PubMedCrossRefGoogle Scholar
  66. Mao, Z. and Nadal-Ginard, B. (1996) Functional and physical interactions between mammalian achaete-scute homolog 1 and myocyte enhancer factor 2A. J. Biol. Chem. 271, 14371–14375.PubMedCrossRefGoogle Scholar
  67. Mao, Z. and Wiedmann, M. (1999) Calcineurin enhances MEF2 DNA binding activity in calcium-dependent survival of cerebellar granule neurons. J. Biol. Chem. 274, 31102–31107.PubMedCrossRefGoogle Scholar
  68. Marinissen, M. J., Chiariello, M., Pallante, M. and 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.PubMedGoogle Scholar
  69. Martin, J. F., Miano, J. M., Hustad, C. M., Copeland, N. G., Jenkins, N. A. and Olson, E. N. (1994) A MEF2 gene that generates a muscle-specific isoform via alternative mRNA splicing. Mol. Cell. Biol. 14, 1647–1656.PubMedGoogle Scholar
  70. McDermott, J. C., Cardoso, M. C., Yu, Y. T., Andres, V., Leifer, D., Krainc, D., Lipton, S. A. and Nadal-Ginard, B. (1993) hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors. Mol. Cell. Biol. 13, 2564–2577.PubMedGoogle Scholar
  71. McKinsey, T. A., Zhang, C. L., Lu, J. and Olson, E. N. (2000) Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408, 106–111.PubMedCrossRefGoogle Scholar
  72. McKinsey, T. A., Zhang, C. L. and Olson, E. N. (2000) Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14–3-3 to histone deacetylase 5. Proc. Natl. Acad. Sci. USA. 97, 14400–14405.PubMedCrossRefGoogle Scholar
  73. McKinsey, T. A., Zhang, C. L. and Olson, E. N. (2001) Control of muscle development by dueling HATs and HDACs. Curr. Opin. Genet. Dev. 11, 497–504.PubMedCrossRefGoogle Scholar
  74. McKinsey, T. A., Zhang, C. L. and Olson, E. N. (2001) Identification of a signal-responsive nuclear export sequence in class II histone deacetylases. Mol. Cell. Biol. 21, 6312–6321.PubMedCrossRefGoogle Scholar
  75. McKinsey, T. A., Zhang, C. L. and Olson, E. N. (2002) MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem. Sci. 27, 40–47.PubMedCrossRefGoogle Scholar
  76. Molkentin, J. D., Black, B. L., Martin, J. F. and Olson, E. N. (1995) Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell 83, 1125–1136.PubMedCrossRefGoogle Scholar
  77. Molkentin, J. D. and 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.PubMedCrossRefGoogle Scholar
  78. Naya, F. J. and Olson, E. (1999) MEF2: a transcriptional target for signaling pathways controlling skeletal muscle growth and differentiation. Curr. Opin. in Cell Biol. 11, 683–688.CrossRefGoogle Scholar
  79. Nebreda, A. R. (2006) CDK activation by non-cyclin proteins. Curr. Opin. in Cell Biol. 18, 192–198.CrossRefGoogle Scholar
  80. Nimchinsky, E. A., Sabatini, B. L. and Svoboda, K. (2002) Structure and function of dendritic spines. Ann. Rev. of Physiol. 64, 313–353.CrossRefGoogle Scholar
  81. O’Hare, M. J., Kushwaha, N., Zhang, Y., Aleyasin, H., Callaghan, S. M., Slack, R. S., Albert, P. R., Vincent, I. and Park, D. S. (2005) Differential roles of nuclear and cytoplasmic cyclin-dependent kinase 5 in apoptotic and excitotoxic neuronal death. J. Neurosci. 25, 8954–8966.PubMedCrossRefGoogle Scholar
  82. Okamoto, S., Krainc, D., Sherman, K. and 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.PubMedCrossRefGoogle Scholar
  83. Okamoto, S., Li, Z., Ju, C., Scholzke, M. N., Mathews, E., Cui, J., Salvesen, G. S., Bossy-Wetzel, E. and Lipton, S. A. (2002) Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis. Proc. Natl. Acad. Sci. USA. 99, 3974–3979.PubMedCrossRefGoogle Scholar
  84. Olson, E. N. and Williams, R. S. (2000) Remodeling muscles with calcineurin. Bioessays 22, 510–519.PubMedCrossRefGoogle Scholar
  85. Ornatsky, O. I., Cox, D. M., Tangirala, P., Andreucci, J. J., Quinn, Z. A., Wrana, J. L., Prywes, R., Yu, Y. T. and McDermott, J. C. (1999) Post-translational control of the MEF2A transcriptional regulatory protein. Nucleic Acids Res. 27, 2646–2654.Google Scholar
  86. Ornatsky, O. I. and 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.PubMedCrossRefGoogle Scholar
  87. Palay, S. L. and Chan-Palay, V. (1974) Cerebellar cortex: cytology and organization. Springer, New York.Google Scholar
  88. Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P. and Tsai, L. H. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622.PubMedCrossRefGoogle Scholar
  89. Ramón y Cajal, S. (1995) Histology of the nervous system of man and vertebrates. Oxford University Press, New York.Google Scholar
  90. Sandmann, T., Jensen, L. J., Jakobsen, J. S., Karzynski, M. M., Eichenlaub, M. P., Bork, P. and Furlong, E. E. (2006) A temporal map of transcription factor activity: MEF2 directly regulates target genes at all stages of muscle development. Dev. Cell 10, 797–807.PubMedCrossRefGoogle Scholar
  91. Schulz, R. A., Chromey, C., Lu, M. F., Zhao, B. and Olson, E. N. (1996) Expression of the D-MEF2 transcription in the Drosophila brain suggests a role in neuronal cell differentiation. Oncogene 12, 1827–1831.PubMedGoogle Scholar
  92. Seeler, J. S. and Dejean, A. (2003) Nuclear and unclear functions of SUMO. Nat. Rev. Mol. Cell Biol. 4, 690–699.PubMedCrossRefGoogle Scholar
  93. Shalizi, A., Gaudilliere, B., Yuan, Z., Stegmuller, J., Shirogane, T., Ge, Q., Tan, Y., Schulman, B., Harper, J. W. and Bonni, A. (2006) A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 311, 1012–1017.PubMedCrossRefGoogle Scholar
  94. Shalizi, A., Lehtinen, M., Gaudilliere, B., Donovan, N., Han, J., Konishi, Y. and Bonni, A. (2003) Characterization of a neurotrophin signaling mechanism that mediates neuron survival in a temporally specific pattern. J. Neurosci. 23, 7326–7336.PubMedGoogle Scholar
  95. Shalizi, A. K. and Bonni, A. (2005) Brawn for Brains: The Role of MEF2 Proteins in the Developing Nervous System. Current topics in Dev. Biol. 69, 239–266.Google Scholar
  96. Shelton, S. B. and Johnson, G. V. (2004) Cyclin-dependent kinase-5 in neurodegeneration. J. Neurochem. 88, 1313–1326.PubMedCrossRefGoogle Scholar
  97. Smith, P. D., Mount, M. P., Shree, R., Callaghan, S., Slack, R. S., Anisman, H., Vincent, I., Wang, X., Mao, Z. and Park, D. S. (2006) Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J. Neurosci. 26, 440–447.PubMedCrossRefGoogle Scholar
  98. Soderling, T. R. (2000) CaM-kinases: modulators of synaptic plasticity. Curr. Opin. in Neurobio. 10, 375–380.CrossRefGoogle Scholar
  99. Soderling, T. R., Chang, B. and Brickey, D. (2001) Cellular signaling through multifunctional Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 276, 3719–3722.PubMedCrossRefGoogle Scholar
  100. Tada, T. and Sheng, M. (2006) Molecular mechanisms of dendritic spine morphogenesis. Curr. Opin. in Neurobio. 16, 95–101.CrossRefGoogle Scholar
  101. Takeda, K., Matsuzawa, A., Nishitoh, H., Tobiume, K., Kishida, S., Ninomiya-Tsuji, J., Matsumoto, K. and Ichijo, H. (2004) Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation. EMBO reports 5, 161–166.PubMedCrossRefGoogle Scholar
  102. Tang, X., Wang, X., Gong, X., Tong, M., Park, D., Xia, Z. and Mao, Z. (2005) Cyclin-dependent kinase 5 mediates neurotoxin-induced degradation of the transcription factor myocyte enhancer factor 2. J. Neurosci. 25, 4823–4834.PubMedCrossRefGoogle Scholar
  103. Tao, X., Finkbeiner, S., Arnold, D. B., Shaywitz, A. J. and Greenberg, M. E. (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20, 709–726.PubMedCrossRefGoogle Scholar
  104. van der Linden, A. M., Nolan, K. M. and Sengupta, P. (2007) KIN-29 SIK regulates chemoreceptor gene expression via an MEF2 transcription factor and a class II HDAC. EMBO J. 26, 358–370.PubMedCrossRefGoogle Scholar
  105. Verdaguer, E., Alvira, D., Jimenez, A., Rimbau, V., Camins, A. and Pallas, M. (2005) Inhibition of the cdk5/MEF2 pathway is involved in the antiapoptotic properties of calpain inhibitors in cerebellar neurons. Brit. J. Pharmacol. 145, 1103–1111.CrossRefGoogle Scholar
  106. Verdin, E., Dequiedt, F. and Kasler, H. G. (2003) Class II histone deacetylases: versatile regulators. Trends Genet. 19, 286–293.PubMedCrossRefGoogle Scholar
  107. Wang, D. Z., Valdez, M. R., McAnally, J., Richardson, J. and Olson, E. N. (2001) The MEF2c gene is a direct transcriptional target of myogenic bHLH and MEF2 proteins during skeletal muscle development. Development 128, 4623–4633.PubMedGoogle Scholar
  108. West, A. E., Chen, W. G., Dalva, M. B., Dolmetsch, R. E., Kornhauser, J. M., Shaywitz, A. J., Takasu, M. A., Tao, X. and Greenberg, M. E. (2001) Calcium regulation of neuronal gene expression. Proc. Natl. Acad. Sci. USA. 98, 11024–11031.PubMedCrossRefGoogle Scholar
  109. Wu, H., Naya, F. J., McKinsey, T. A., Mercer, B., Shelton, J. M., Chin, E. R., Simard, A. R., Michel, R. N., Bassel-Duby, R., Olson, E. N. and Williams, R. S. (2000) MEF2 responds to multiple calcium-regulated signals in the control of skeletal muscle fiber type. EMBO J. 19, 1963–1973.PubMedCrossRefGoogle Scholar
  110. Wu, H., Rothermel, B., Kanatous, S., Rosenberg, P., Naya, F. J., Shelton, J. M., Hutcheson, K. A., DiMaio, J. M., Olson, E. N., Bassel-Duby, R. and Williams, R. S. (2001) Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway. EMBO J. 20, 6414–6423.PubMedCrossRefGoogle Scholar
  111. Yang, C. C., Ornatsky, O. I., McDermott, J. C., Cruz, T. F. and 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.PubMedCrossRefGoogle Scholar
  112. Yang, S. H., Galanis, A. and Sharrocks, A. D. (1999) Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors. Mol. Cell. Biol. 19, 4028–4038.PubMedGoogle Scholar
  113. Zhang, C. L., McKinsey, T. A., Chang, S., Antos, C. L., Hill, J. A. and Olson, E. N. (2002) Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488.PubMedCrossRefGoogle Scholar
  114. Zhao, M., New, L., Kravchenko, V. V., Kato, Y., Gram, H., di Padova, F., Olson, E. N., Ulevitch, R. J. and Han, J. (1999) Regulation of the MEF2 family of transcription factors by p38. Mol. Cell. Biol. 19, 21–30.PubMedGoogle Scholar
  115. Zhao, X., Sternsdorf, T., Bolger, T. A., Evans, R. M. and Yao, T. P. (2005) Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol. Cell. Biol. 25, 8456–8464.PubMedCrossRefGoogle Scholar
  116. Zhu, B. and Gulick, T. (2004) Phosphorylation and alternative pre-mRNA splicing converge to regulate myocyte enhancer factor 2C activity. Mol. Cell. Biol. 24, 8264–8275.PubMedCrossRefGoogle Scholar
  117. Zhu, B., Ramachandran, B. and Gulick, T. (2005) Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain. J. Biol. Chem. 280, 28749–28760.PubMedCrossRefGoogle Scholar
  118. Zuo, Y., Lin, A., Chang, P. and Gan, W. B. (2005) Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46, 181–189.PubMedCrossRefGoogle Scholar
  119. Zuo, Y., Yang, G., Kwon, E. and Gan, W. B. (2005) Long-term sensory deprivation prevents dendritic spine loss in primary somatosensory cortex. Nature 436, 261–265.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Aryaman Shalizi
  • Azad Bonni

There are no affiliations available

Personalised recommendations