RRC ID 5442
Author Liu Y, Padgett D, Takahashi M, Li H, Sayeed A, Teichert RW, Olivera BM, McArdle JJ, Green WN, Lin W.
Title Essential roles of the acetylcholine receptor gamma-subunit in neuromuscular synaptic patterning.
Journal Development
Abstract Formation of the vertebrate neuromuscular junction (NMJ) takes place in a stereotypic pattern in which nerves terminate at select sarcolemmal sites often localized to the central region of the muscle fibers. Several lines of evidence indicate that the muscle fibers may initiate postsynaptic differentiation independent of the ingrowing nerves. For example, nascent acetylcholine receptors (AChRs) are pre-patterned at select regions of the muscle during the initial stage of neuromuscular synaptogenesis. It is not clear how these pre-patterned AChR clusters are assembled, and to what extent they contribute to pre- and post-synaptic differentiation during development. Here, we show that genetic deletion of the AChR gamma-subunit gene in mice leads to an absence of pre-patterned AChR clusters during initial stages of neuromuscular synaptogenesis. The absence of pre-patterned AChR clusters was associated with excessive nerve branching, increased motoneuron survival, as well as aberrant distribution of acetylcholinesterase (AChE) and rapsyn. However, clustering of muscle specific kinase (MuSK) proceeded normally in the gamma-null muscles. AChR clusters emerged at later stages owing to the expression of the AChR epsilon-subunit, but these delayed AChR clusters were broadly distributed and appeared at lower level compared with the wild-type muscles. Interestingly, despite the abnormal pattern, synaptic vesicle proteins were progressively accumulated at individual nerve terminals, and neuromuscular synapses were ultimately established in gamma-null muscles. These results demonstrate that the gamma-subunit is required for the formation of pre-patterned AChR clusters, which in turn play an essential role in determining the subsequent pattern of neuromuscular synaptogenesis.
Volume 135(11)
Pages 1957-67
Published 2008-6-1
DOI 10.1242/dev.018119
PII dev.018119
PMID 18434415
PMC PMC2650015
MeSH Acetylcholinesterase / metabolism Animals Cell Survival / genetics Cell Survival / physiology Electrophysiology Immunohistochemistry Mice Mice, Mutant Strains Motor Neurons / cytology Motor Neurons / metabolism Motor Neurons / physiology Muscle Proteins / metabolism Muscles / embryology Muscles / metabolism Neuromuscular Junction / embryology Neuromuscular Junction / genetics Neuromuscular Junction / metabolism* Organogenesis / genetics Organogenesis / physiology* Receptor Protein-Tyrosine Kinases / metabolism Receptors, Cholinergic / genetics Receptors, Cholinergic / metabolism Receptors, Cholinergic / physiology* Reverse Transcriptase Polymerase Chain Reaction
IF 5.611
Times Cited 40
Mice RBRC00235