Characterization of a muscle-specific enhancer in human MuSK promoter reveals the essential role of myogenin in controlling activity-dependent gene regulation.
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(alphabeta) 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.
Tang
Huibin
H
Molecular and Behavior Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, 48109, USA.
Veldman
Matthew B
MB
Goldman
Daniel
D
D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism*; D018008:Myogenin / Q000502:physiology*; D011401:Promoter Regions, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics; D015533:Transcriptional Activation; D015027:Zebrafish / Q000378:metabolism
D018008:Myogenin; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D002118:Calcium