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Postnatal knockdown of dok‐7 gene expression in mice causes structural defects in neuromuscular synapses and myasthenic pathology
Author(s) -
Eguchi Takahiro,
Tezuka Tohru,
Miyoshi Sadanori,
Yamanashi Yuji
Publication year - 2016
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12370
Subject(s) - biology , neuromuscular junction , gene knockdown , congenital myasthenic syndrome , microbiology and biotechnology , synapse , skeletal muscle , endocrinology , acetylcholine receptor , medicine , gene , receptor , neuroscience , genetics
The neuromuscular junction (NMJ) is a synapse between a motor neuron and skeletal muscle and is required for muscle contraction. The formation and maintenance of NMJs are governed by the muscle‐specific receptor tyrosine kinase MuSK. We previously showed that the muscle cytoplasmic protein Dok‐7 is an essential activator of MuSK. Indeed, mice lacking either Dok‐7 or MuSK form no NMJs, and defects in the human DOK7 gene underlie a congenital myasthenic syndrome (an NMJ disorder). However, it remains unproven whether Dok‐7 is required for the postnatal maintenance of NMJs. In this study, we generated recombinant adeno‐associated virus (AAV) vectors encoding short hairpin RNAs targeting the mouse dok‐7 gene (AAV‐shD7). Systemic administration of AAV‐shD7 into 2‐week‐old mice down‐regulated dok‐7 expression in muscle and induced myasthenic symptoms including reduction in body weight and motor function. Moreover, AAV‐shD7 treatment suppressed MuSK‐dependent gene expression of NMJ components and reduced the size of NMJs. These results demonstrate that correct, physiological levels of dok‐7 expression are required for the postnatal maintenance of NMJs.