Molecular Mechanisms Mediating Synapse-Specific Gene Expression During Development of the Neuromuscular Junction

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Abstract
Adult skeletal muscle locally expresses nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction by selective induction of their subunit-encoding genes (αβεδ) in endplate-associated myonuclei. Neuregulin/ARIA is a nerve-derived factor that is thought to be largely responsible for this local gene induction, Neuregulin/ARIA activates a Ras/MAP kinase signalling cascade, which ultimately induces nAChR ε-subunit gene expression via a 15 bp sequence that harbors a core Ets transcription factor binding site (GGA). Interestingly, this same sequence also appears to participate in extrajunctional repression of the ε-subunit gene. Muscle Ets 2 overexpression induces nAChR ε-subunit gene promoter activity, whereas a dominant/negative Ets blocks neuregulin-dependent induction. These results suggest that Ets transcription factors play a role in mediating synapse-specific and neuregulin-mediated motor neuron control of nAChR gene expression. Key words: nicotinic acetylcholine receptor, Ras, MAP kinase. Ets transcription factors, neuregulin, protein tyrosine phosphatases

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