A mechanism in agrin signaling revealed by a prevalent Rapsyn mutation in congenital myasthenic syndrome

eLife

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[1] Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, United States;Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States;Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States;Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, United States;Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States;Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, United States;

关键词: neuromuscular junction;    congenital myasthenic syndrome;    acetylcholine receptor;    Rapsyn;    Mouse;   

DOI  :  10.7554/eLife.49180

来源: publisher

【 摘 要 】

10.7554/eLife.49180.001Neuromuscular 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.

【 授权许可】

CC BY