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

Full 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.

Author information

Author/s: Ponomareva, Olga N (ON); 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);

Affiliation: Section of Neurobiology and Institute for Neuroscience, University of Texas at Austin, Austin, TX 78712-0248, USA.

Grants: GM065797 (Agency:NIGMS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Molecular and cellular neurosciences (Mol Cell Neurosci), published in United States. (Language: eng)

Reference: 2006-Feb; vol 31 (issue 2) : pp 334-45

Dates: Created 2006/02/13; Completed 2006/06/13; Revised 2007/11/14;

PMID: 16278083, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: 18 Feb 2009 00:00:00)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Agrin - genetics; metabolism
Animals
Mice
Mice, Transgenic
Muscle, Skeletal - cytology; embryology; metabolism
Neuromuscular Junction - embryology; metabolism
Protein Isoforms - genetics; metabolism

Protein Isoforms - genetics; metabolism
Receptor Protein-Tyrosine Kinases - genetics; metabolism
Receptor, erbB-2 - genetics; metabolism
Receptors, Cholinergic - genetics; metabolism
Signal Transduction - physiology
Synapses - physiology
Tyrosine - metabolism

Associated Chemicals: Agrin (0) ; Protein Isoforms (0) ; Receptors, Cholinergic (0) ; Tyrosine (55520-40-6) ; Receptor Protein-Tyrosine Kinases (EC 2.7.1.112) ; Receptor, erbB-2 (EC 2.7.1.112) ; MUSK protein, human (EC 2.7.10.1)

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