期刊
GENES TO CELLS
卷 21, 期 6, 页码 670-676出版社
WILEY-BLACKWELL
DOI: 10.1111/gtc.12370
关键词
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资金
- JSPS KAKENHI [25460357]
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [B-15]
- Grants-in-Aid for Scientific Research [25117708, 16K14575, 14J08885, 25460357] Funding Source: KAKEN
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.
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