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Defective neuromuscular synaptogenesis in mice expressing constitutively active ErbB2 in skeletal muscle fibers
Olga N Ponomareva1, Hualong Ma, Vita M Vock
1Section of Neurobiology and Institute for Neuroscience, University of Texas at Austin, Austin, TX 78712-0248, USA.
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.
Insights
Overexpressing a constitutively active form of the neuregulin receptor ErbB2 (CAErbB2) in skeletal muscle caused embryonic lethality and impaired synapse formation. This ErbB2 signaling disruption mimics agrin deficiency by affecting acetylcholine receptor clustering.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Neuregulin receptor ErbB2 plays a role in neuronal development and function.
- Proper neuromuscular junction formation requires intricate signaling between motor neurons and muscle fibers.
Purpose of the Study:
- To investigate the in vivo and in vitro effects of overexpressing a constitutively active form of ErbB2 (CAErbB2) in skeletal muscle fibers.
- To elucidate the role of ErbB2 signaling in synaptogenesis and acetylcholine receptor (AChR) clustering.
Main Methods:
- Utilized tetracycline-inducible expression to overexpress CAErbB2 in skeletal muscle fibers both in vivo and in vitro.
- Analyzed embryonic development, synaptogenesis, axonal sprouting, and AChR transcript distribution.
- Assessed the impact of CAErbB2 expression on agrin-induced AChR cluster formation in cultured myotubes.
- Measured tyrosine phosphorylation levels of MuSK and AChRbeta subunits.
Main Results:
- CAErbB2 expression during embryonic development was lethal and led to impaired synaptogenesis, characterized by loss of synaptic contacts and extensive axonal sprouting.
- A phenotype resembling agrin-deficient mice was observed, with diffuse AChR transcript distribution.
- CAErbB2 expression in cultured myotubes inhibited agrin-induced AChR cluster formation and maintenance.
- While MuSK tyrosine phosphorylation remained similar, AChRbeta subunit tyrosine phosphorylation was significantly reduced in CAErbB2-expressing embryos.
Conclusions:
- Gain-of-function manipulation of ErbB2 signaling in skeletal muscle induces an agrin-deficient-like phenotype.
- The defect in AChR clustering originates from the muscle fiber, not the nerve.
- ErbB2 signaling dysregulation uncouples MuSK and AChR tyrosine phosphorylation, disrupting neuromuscular junction formation.
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