ETS transcription factor Erm controls subsynaptic gene expression in skeletal muscles.
Accumulation of specific proteins at synaptic structures is essential for synapse assembly and function, but mechanisms regulating local protein enrichment remain poorly understood. At the neuromuscular junction (NMJ), subsynaptic nuclei underlie motor axon terminals within extrafusal muscle fibers and are transcriptionally distinct from neighboring nuclei. In this study, we show that expression of the ETS transcription factor Erm is highly concentrated at subsynaptic nuclei, and its mutation in mice leads to severe downregulation of many genes with normally enriched subsynaptic expression. Erm mutant mice display an expansion of the muscle central domain in which acetylcholine receptor (AChR) clusters accumulate, show gradual fragmentation of AChR clusters, and exhibit symptoms of muscle weakness mimicking congenital myasthenic syndrome (CMS). Together, our findings define Erm as an upstream regulator of a transcriptional program selective to subsynaptic nuclei at the NMJ and underscore the importance of transcriptional control of local synaptic protein accumulation.
Hippenmeyer
Simon
S
Biozentrum, Department of Cell Biology, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
Huber
Roland M
RM
Ladle
David R
DR
Murphy
Kenneth
K
Arber
Silvia
S
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009157:Myasthenia Gravis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D011940:Receptor Aggregation / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics