title: The role of MuSK in synapse formation and neuromuscular disease.
abstract: Muscle-specific kinase (MuSK) is essential for each step in neuromuscular synapse formation. Before innervation, MuSK initiates postsynaptic differentiation, priming the muscle for synapse formation. Approaching motor axons recognize the primed, or prepatterned, region of muscle, causing motor axons to stop growing and differentiate into specialized nerve terminals. MuSK controls presynaptic differentiation by causing the clustering of Lrp4, which functions as a direct retrograde signal for presynaptic differentiation. Developing synapses are stabilized by neuronal Agrin, which is released by motor nerve terminals and binds to Lrp4, a member of the low-density lipoprotein receptor family, stimulating further association between Lrp4 and MuSK and increasing MuSK kinase activity. In addition, MuSK phosphorylation is stimulated by an inside-out ligand, docking protein-7 (Dok-7), which is recruited to tyrosine-phosphorylated MuSK and increases MuSK kinase activity. Mutations in MuSK and in genes that function in the MuSK signaling pathway, including Dok-7, cause congenital myasthenia, and autoantibodies to MuSK, Lrp4, and acetylcholine receptors are responsible for myasthenia gravis.
authors: Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU Medical School, New York, NY 10016, USA.
authors: Steven J
authors: SJ
authors: Burden
authors: Norihiro
authors: N
authors: Yumoto
authors: Wei
authors: W
authors: Zhang
mesh_terms: D018171:Agrin / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D008954:Models, Biological; D009132:Muscles / Q000166:cytology / Q000294:innervation / Q000473:pathology; D009157:Myasthenia Gravis / Q000235:genetics* / Q000473:pathology; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
chemical_list: D018171:Agrin; D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human; D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases
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