title: Inhibition of synapse assembly in mammalian muscle in vivo by RNA interference.
abstract: The formation of the vertebrate neuromuscular junction (NMJ) requires the receptor tyrosine kinase MuSK and the adaptor molecule rapsyn. Here, we report that the phenotypes of mice deficient in these two molecules can be reproduced by RNA interference (RNAi) in rat muscle in vivo. Specifically, double-stranded RNA (dsRNA) targeting MuSK and rapsyn inhibited the formation of the NMJ in rat muscle fibres in vivo, while dsRNA targeting nonessential proteins did not have any effect. Moreover, plasmids that trigger RNAi to MuSK induced the disassembly of existing NMJs. These results thus demonstrate for the first time the functionality of dsRNA in silencing endogenous genes in adult mammalian muscle in vivo. Moreover, they show that MuSK is also required for the maintenance of the NMJ, offering a mechanistic explanation for the myasthenia gravis caused by auto-antibodies to MuSK.
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Xian Chu
authors.initials: XC
authors.lastname: Kong
authors.forename: Patrizia
authors.initials: P
authors.lastname: Barzaghi
authors.forename: Markus A
authors.initials: MA
authors.lastname: Ruegg
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009132:Muscles / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000235:genetics / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011950:Receptors, Cholinergic / Q000235:genetics; D049411:Utrophin / Q000235:genetics / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D016189:Dystrophin; D009124:Muscle Proteins; D012330:RNA, Double-Stranded; D011950:Receptors, Cholinergic; D049411:Utrophin; C051609:peripheral membrane protein 43K; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases