Defective neuromuscular synaptogenesis in mice expressing constitutively active ErbB2 in skeletal muscle fibers.
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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.
author list (cited authors)
Ponomareva, O. N., Ma, H., Vock, V. M., Ellerton, E. L., Moody, S. E., Dakour, R., Chodosh, L. A., & Rimer, M.
complete list of authors
Ponomareva, Olga N||Ma, Hualong||Vock, Vita M||Ellerton, Elaine L||Moody, Susan E||Dakour, Ramzi||Chodosh, Lewis A||Rimer, Mendell