title: Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of α-dystrobrevin.
abstract: Neuregulin (NRG)/ErbB signaling is involved in numerous developmental processes in the nervous system, including synapse formation and function in the central nervous system. Although intensively investigated, its role at the neuromuscular synapse has remained elusive. Here, we demonstrate that loss of neuromuscular NRG/ErbB signaling destabilized anchoring of acetylcholine receptors (AChRs) in the postsynaptic muscle membrane and that this effect was caused by dephosphorylation of α-dystrobrevin1, a component of the postsynaptic scaffold. Specifically, in mice in which NRG signaling to muscle was genetically or pharmacologically abolished, postsynaptic AChRs moved rapidly from the synaptic to the perisynaptic membrane, and the subsynaptic scaffold that anchors the AChRs was impaired. These defects combined compromised synaptic transmission. We further show that blockade of NRG/ErbB signaling abolished tyrosine phosphorylation of α-dystrobrevin1, which reduced the stability of receptors in agrin-induced AChR clusters in cultured myotubes. Our data indicate that NRG/ErbB signaling maintains high efficacy of synaptic transmission by stabilizing the postsynaptic apparatus via phosphorylation of α-dystrobrevin1.
authors.affiliation: Institute of Physiology, Department of Biomedicine, University of Basel, CH-4056, Basel, Switzerland.
authors.forename: Nadine
authors.initials: N
authors.lastname: Schmidt
authors.forename: Mohammed
authors.initials: M
authors.lastname: Akaaboune
authors.forename: Nadesan
authors.initials: N
authors.lastname: Gajendran
authors.forename: Isabel
authors.initials: I
authors.lastname: Martinez-Pena y Valenzuela
authors.forename: Sarah
authors.initials: S
authors.lastname: Wakefield
authors.forename: Raphael
authors.initials: R
authors.lastname: Thurnheer
authors.forename: Hans Rudolf
authors.initials: HR
authors.lastname: Brenner
mesh_terms: D018171:Agrin / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D049029:Dystrophin-Associated Proteins / Q000378:metabolism*; D066246:ErbB Receptors / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D020880:Neuregulins / Q000172:deficiency / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D066247:Receptor, ErbB-4; D011950:Receptors, Cholinergic / Q000378:metabolism; D015398:Signal Transduction; D013570:Synaptic Membranes / Q000378:metabolism
chemical_list: D018171:Agrin; D049029:Dystrophin-Associated Proteins; D066246:ErbB Receptors; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D011950:Receptors, Cholinergic; C098885:dystrobrevin; C524056:Erbb2 protein, mouse; C587690:Erbb4 protein, mouse