Defective neuromuscular synaptogenesis in mice expressing constitutively active ErbB2 in skeletal muscle fibers.
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.
Ponomareva
Olga N
ON
Section of Neurobiology and Institute for Neuroscience, University of Texas at Austin, Austin, TX 78712-0248, USA.
Ma
Hualong
H
Vock
Vita M
VM
Ellerton
Elaine L
EL
Moody
Susan E
SE
Dakour
Ramzi
R
Chodosh
Lewis A
LA
Rimer
Mendell
M
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
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