Abstract
Neuromuscular junction is a synapse between motoneurons and skeletal muscles, where acetylcholine receptors (AChRs) are concentrated to control muscle contraction. Studies of this synapse have contributed to our understanding of synapse assembly and pathological mechanisms of neuromuscular disorders. Nevertheless, underlying mechanisms of NMJ formation was not well understood. To this end, we took a novel approach - studying mutant genes implicated in congenital myasthenic syndrome (CMS). We showed that knock-in mice carrying N88K, a prevalent CMS mutation of Rapsyn (Rapsn), died soon after birth with profound NMJ deficits. Rapsn is an adapter protein that bridges AChRs to the cytoskeleton and possesses E3 ligase activity. In investigating how N88K impairs the NMJ, we uncovered a novel signaling pathway by which Agrin-LRP4-MuSK induces tyrosine phosphorylation of Rapsn, which is required for its self-association and E3 ligase activity. Our results also provide insight into pathological mechanisms of CMS.
Highlights
The neuromuscular junction (NMJ) is a synapse between motoneurons and muscle fibers
Axon terminals were extensively arborized in N88K mt mice, with increased secondary and tertiary nerve branches and reduced density of synaptic vesicles phenotypes observed in mt mice lacking LRP4 or MuSK (DeChiara et al, 1996; Weatherbee et al, 2006; Wu et al, 2012b)
Agrin is a factor utilized by motoneurons to direct NMJ formation, in particular postsynaptic differentiation (McMahan, 1990)
Summary
The neuromuscular junction (NMJ) is a synapse between motoneurons and muscle fibers. At vertebrate NMJs, motor nerve terminals release acetylcholine (ACh), which activates ACh receptors (AChRs) concentrated on postsynaptic membranes to initiate muscle contraction. Rapsn, discovered as a peripheral membrane protein associated with AChRs in the electric organ of Torpedo (Cohen et al, 1972; Neubig and Cohen, 1979; Porter and Froehner, 1985), colocalizes with AChRs at developing as well as adult NMJs (Froehner et al, 1981; Noakes et al, 1993; Sealock et al, 1984) It could induce AChR clusters in heterologous cells (Froehner et al, 1990; Li et al, 2016; Phillips et al, 1991); Rapsn null mutant mice die soon after birth without AChR clusters (Gautam et al, 1995), indicating a critical role in NMJ formation. Our results unravel pathophysiological mechanisms of N88K mutation, and provide novel insight into how signals are transduced from Agrin-LRP4-MuSK to Rapsn
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