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Science 312 (5781): 1802-1805

Copyright © 2006 by the American Association for the Advancement of Science

The Muscle Protein Dok-7 Is Essential for Neuromuscular Synaptogenesis

Kumiko Okada,1* Akane Inoue,1* Momoko Okada,1 Yoji Murata,1 Shigeru Kakuta,3 Takafumi Jigami,4 Sachiko Kubo,3 Hirokazu Shiraishi,5 Katsumi Eguchi,5 Masakatsu Motomura,5 Tetsu Akiyama,4 Yoichiro Iwakura,3 Osamu Higuchi,1{dagger} Yuji Yamanashi1,2{dagger}

Abstract: The formation of the neuromuscular synapse requires muscle-specific receptor kinase (MuSK) to orchestrate postsynaptic differentiation, including the clustering of receptors for the neurotransmitter acetylcholine. Upon innervation, neural agrin activates MuSK to establish the postsynaptic apparatus, although agrin-independent formation of neuromuscular synapses can also occur experimentally in the absence of neurotransmission. Dok-7, a MuSK-interacting cytoplasmic protein, is essential for MuSK activation in cultured myotubes; in particular, the Dok-7 phosphotyrosine-binding domain and its target in MuSK are indispensable. Mice lacking Dok-7 formed neither acetylcholine receptor clusters nor neuromuscular synapses. Thus, Dok-7 is essential for neuromuscular synaptogenesis through its interaction with MuSK.

1 Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113–8510, Japan.
2 School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113–8510, Japan.
3 Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108–8639, Japan.
4 Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113–0032, Japan.
5 The First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852–8501, Japan.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: yamanashi.creg{at}mri.tmd.ac.jp (Y.Y.); higuchi.creg{at}mri.tmd.ac.jp (O.H.)

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