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J. Biol. Chem., Vol. 281, Issue 7, 3943-3953, February 17, 2006

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Characterization of a Muscle-specific Enhancer in Human MuSK Promoter Reveals the Essential Role of Myogenin in Controlling Activity-dependent Gene Regulation^*

From the Molecular and Behavior Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109

Neuromuscular synaptogenesis is initiated by the release of agrin from motor neurons and the activation of the receptor tyrosine kinase, MuSK, in the postsynaptic membrane. MuSK gene expression is regulated by nerve-derived agrin and muscle activity. Agrin stimulates synapse-specific MuSK gene expression by activating GABP transcription factors in endplate-associated myonuclei. In contrast, the mechanism by which muscle activity regulates MuSK gene expression is not known. We report on a 60-bp MuSK enhancer that confers promoter regulation by muscle differentiation, changes in intracellular calcium, and muscle activity. Within this enhancer, we identified a single E-box that is essential for this regulation. This E-box binds myogenin, and we showed that myogenin is necessary for not only MuSK but also nAChR gene regulation by muscle activity. Surprisingly, the same E-box functions in vivo to mediate muscle-specific and differentiation-dependent gene induction in zebrafish, suggesting an evolutionary conserved mechanism of regulation of synaptic protein gene expression.

Received for publication, October 18, 2005 , and in revised form, November 9, 2005.

^* This work was supported by NINDS, National Institutes of Health, Grant RO1 NS25153. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109. Tel.: 734-936-2057; Fax: 734-647-4130; E-mail: neuroman{at}umich.edu.

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This article has been cited by other articles:

				H. Tang, P. Macpherson, M. Marvin, E. Meadows, W. H. Klein, X.-J. Yang, and D. Goldman A Histone Deacetylase 4/Myogenin Positive Feedback Loop Coordinates Denervation-dependent Gene Induction and Suppression Mol. Biol. Cell, February 1, 2009; 20(4): 1120 - 1131. [Abstract] [Full Text] [PDF]

				H. Tang and D. Goldman Activity-dependent gene regulation in skeletal muscle is mediated by a histone deacetylase (HDAC)-Dach2-myogenin signal transduction cascade PNAS, November 7, 2006; 103(45): 16977 - 16982. [Abstract] [Full Text] [PDF]