Synaptic differentiation is defective in mice lacking acetylcholine receptor beta-subunit tyrosine phosphorylation.
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- beta(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.
Friese
Matthew B
MB
Molecular Neurobiology Program, The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU Medical School, 540 First Avenue, New York, NY 10016, USA.
Blagden
Chris S
CS
Burden
Steven J
SJ
D000818:Animals; D002454:Cell Differentiation; D017931:DNA Primers; D004594:Electrophysiology; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000502:physiology; D009469:Neuromuscular Junction / Q000502:physiology / Q000648:ultrastructure; D019000:Phosphotyrosine / Q000172:deficiency*; D016133:Polymerase Chain Reaction; D021122:Protein Subunits / Q000172:deficiency*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000172:deficiency* / Q000235:genetics; D013569:Synapses / Q000235:genetics* / Q000502:physiology / Q000648:ultrastructure
C495964:Chrnb1 protein, mouse; D017931:DNA Primers; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D019000:Phosphotyrosine; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases