Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation.
The formation of the neuromuscular junction (NMJ) is orchestrated by the muscle-specific receptor tyrosine kinase MuSK and by neural agrin, an extracellular activator of MuSK. We previously showed that the MuSK-interacting protein Dok-7 is essential for neuromuscular synaptogenesis, although the mechanisms by which Dok-7 regulates MuSK activity and promotes synapse formation have been unclear. Here, we show that Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the receptor tyrosine kinase, and that neural agrin requires Dok-7 to activate MuSK. In vivo overexpression of Dok-7 increased MuSK activation and promoted NMJ formation. Furthermore, Dok-7 was required for the localization of MuSK in the central region of muscle, which is essential for the correct formation of NMJs in this region. These observations indicate that Dok-7 positively regulates neuromuscular synaptogenesis by controlling MuSK activity, its distribution, and its responsiveness to neural agrin.
Inoue
Akane
A
Division of Genetics and Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Setoguchi
Kiyoko
K
Matsubara
Yosuke
Y
Okada
Kumiko
K
Sato
Nozomi
N
Iwakura
Yoichiro
Y
Higuchi
Osamu
O
Yamanashi
Yuji
Y
D018171:Agrin; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
D018171:Agrin; C511692:DOK7 protein, human; D009124:Muscle Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases