title: Defective neuromuscular synaptogenesis in mice expressing constitutively active ErbB2 in skeletal muscle fibers.
abstract: We overexpressed a constitutively active form of the neuregulin receptor ErbB2 (CAErbB2) in skeletal muscle fibers in vivo and in vitro by tetracycline-inducible expression. Surprisingly, CAErbB2 expression during embryonic development was lethal and impaired synaptogenesis yielding a phenotype with loss of synaptic contacts, extensive axonal sprouting, and diffuse distribution of acetylcholine receptor (AChR) transcripts, reminiscent of agrin-deficient mice. CAErbB2 expression in cultured myotubes inhibited the formation and maintenance of agrin-induced AChR clusters, suggesting a muscle- and not a nerve-origin for the defect in CAErbB2-expressing mice. Levels of tyrosine phosphorylated MuSK, the signaling component of the agrin receptor, were similar, while tyrosine phosphorylation of AChRbeta subunits was dramatically reduced in CAErbB2-expressing embryos relative to controls. Thus, a gain-of-function manipulation of ErbB2 signaling pathways renders an agrin-deficient-like phenotype that uncouples MuSK and AChR tyrosine phosphorylation.
authors.affiliation: Section of Neurobiology and Institute for Neuroscience, University of Texas at Austin, Austin, TX 78712-0248, USA.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Ponomareva
authors.forename: Hualong
authors.initials: H
authors.lastname: Ma
authors.forename: Vita M
authors.initials: VM
authors.lastname: Vock
authors.forename: Elaine L
authors.initials: EL
authors.lastname: Ellerton
authors.forename: Susan E
authors.initials: SE
authors.lastname: Moody
authors.forename: Ramzi
authors.initials: R
authors.lastname: Dakour
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
authors.forename: Mendell
authors.initials: M
authors.lastname: Rimer
mesh_terms: D018171:Agrin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D009469:Neuromuscular Junction / Q000196:embryology* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D018171:Agrin; D020033:Protein Isoforms; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011950:Receptors, Cholinergic; D014443:Tyrosine; C095714:MUSK protein, human