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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 et al. (Tue,) studied this question.