Defective neuromuscular synaptogenesis in mice expressing constitutively active ErbB2 in skeletal muscle fibers

• Published in: Molecular and cellular neuroscience Vol. 31; no. 2; pp. 334 - 345
• Main Authors: Ponomareva, Olga N., Ma, Hualong, Vock, Vita M., Ellerton, Elaine L., Moody, Susan E., Dakour, Ramzi, Chodosh, Lewis A., Rimer, Mendell
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2006
• Subjects: Agrin - genetics; Agrin - metabolism; Animals; Mice; Mice, Transgenic; Muscle, Skeletal - cytology; Muscle, Skeletal - embryology; Muscle, Skeletal - metabolism; Neuromuscular Junction - embryology; Neuromuscular Junction - metabolism; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptors, Cholinergic - genetics; Receptors, Cholinergic - metabolism; Signal Transduction - physiology; Synapses - physiology; Tyrosine - metabolism
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2005.10.004

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 AChRβ 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.