期刊
DEVELOPMENT
卷 134, 期 23, 页码 4167-4176出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.010702
关键词
AChR clustering; junctional folds; neuromuscular junction; synaptogenesis; chrnb1
资金
- NIGMS NIH HHS [T32 GM007308] Funding Source: Medline
- NINDS NIH HHS [R01 NS036193, R01 NS027963, NS36193, F30 NS054418] Funding Source: Medline
Agrin activates MuSK, a receptor tyrosine kinase expressed in skeletal muscle, leading to tyrosine phosphorylation of the acetylcholine receptor (AChR) beta-subunit and clustering of AChRs. The importance of AChR beta-subunit tyrosine phosphorylation in clustering AChRs and regulating synaptic differentiation is poorly understood. We generated mice with targeted mutations in the three intracellular tyrosines of the AChR beta-subunit (AChR-beta(3F/3F)). Mice lacking AChR beta-subunit tyrosine phosphorylation thrive postnatally and have no overt behavioral defects, indicating that AChR beta-subunit tyrosine phosphorylation is not essential for the formation of neuromuscular synapses. Nonetheless, the size of synapses and the density of synaptic AChRs are reduced in AChR-(3F/3F) mutant mice. Moreover, synapses are structurally simplified and the organization of postjunctional folds is aberrant in mice lacking tyrosine phosphorylation of the AChR beta-subunit. Furthermore, mutant AChRs cluster poorly in response to agrin and are readily extracted from the cell surface of cultured myotubes by non-ionic detergent. These data indicate that tyrosine phosphorylation of the AChR beta-subunit has an important role in organizing AChRs and regulating synaptic differentiation. DEVELOPMENT
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