Molecular mechanisms mediating synapse-specific gene expression during development of the neuromuscular junction.
Adult skeletal muscle locally expresses nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction by selective induction of their subunit-encoding genes (alpha beta epsilon delta) 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 epsilon-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 epsilon-subunit gene. Muscle Ets 2 overexpression induces nAChR epsilon-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.
Mental Health Research Institute, University of Michigan, Ann Arbor 48109, USA.
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D000328:Adult; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D009045:Motor Endplate / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000294:innervation; D009414:Nerve Growth Factors / Q000235:genetics; D020880:Neuregulins; D009469:Neuromuscular Junction / Q000254:growth & development*; D011401:Promoter Regions, Genetic; D011950:Receptors, Cholinergic / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D018631:ras Proteins / Q000235:genetics
D006023:Glycoproteins; D009414:Nerve Growth Factors; D020880:Neuregulins; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; D014157:Transcription Factors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018631:ras Proteins