Ruth Herbst1, Maartje G. Huijbers2,3, Julien Oury4 and Steven J. Burden5 1Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria 2Department of Human Genetics, Leiden University Medical Centre LUMC, 2300 RC Leiden, the Netherlands 3Department of Neurology, Leiden University Medical Centre LUMC, 2333 ZA Leiden, the Netherlands 4Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, New York 10016, USA 5Neurology Department, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA Correspondence: sburdenmgh.harvard.edu

A coordinated and complex interplay of signals between motor neurons, skeletal muscle cells, and Schwann cells controls the formation and maintenance of neuromuscular synapses. Deficits in the signaling pathway for building synapses, caused by mutations in critical genes or autoantibodies against key proteins, are responsible for several neuromuscular diseases, which cause muscle weakness and fatigue. Here, we describe the role that four key genes, Agrin, Lrp4, MuSK, and Dok7, play in this signaling pathway, how an understanding of their mechanisms of action has led to an understanding of several neuromuscular diseases, and how this knowledge has contributed to emerging therapies for treating neuromuscular diseases.