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DOK7 Promotes NMJ Regeneration After Nerve Injury

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Abstract

Motor function recovery from injury requires the regeneration of not only muscle fibers, but also the neuromuscular junction—the synapse between motor nerve terminals and muscle fibers. However, unlike muscle regeneration which has been extensively studied, little is known about the molecular mechanisms of NMJ regeneration. Recognizing the critical role of agrin-LRP4-MuSK signaling in NMJ formation and maintenance, we investigated whether increasing MuSK activity promotes NMJ regeneration. To this end, we evaluated the effect of DOK7, a protein that stimulates MuSK, on NMJ regeneration. Reinnervation, AChR cluster density, and endplate area were improved, and fragmentation was reduced in the AAV9-DOK7-GFP-injected muscles compared with muscles injected with AAV9-GFP. These results demonstrated expedited NMJ regeneration associated with increased DOK7 expression and support the hypothesis that increasing agrin signaling benefits motor function recovery after injury. Our findings propose a potentially new therapeutic strategy for functional recovery after muscle and nerve injury, i.e., promoting NMJ regeneration by increasing agrin signaling.

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Data Availability

The datasets generated during and/or analyzed during the current study are available (upon request) in the Mei Lab repository at the Department of Neuroscience, Case Western Reserve University (contact email: ekosco3@yahoo.com).

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Acknowledgements

We appreciate Mei and Xiong laboratory members of Case Western Reserve University for constructive discussions.

Funding

This work was supported by the VA Merit Award (5I01BX001020-08).

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Authors and Affiliations

  1. Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, 44106, USA

    Ethan D. Kosco, Wen-Cheng Xiong, Ivy S. Samuels & Lin Mei

  2. Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA

    Hongyang Jing, Peng Chen, Wen-Cheng Xiong & Lin Mei

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Contributions

Lin Mei and Wen-Cheng Xiong contributed to the study conception and design. Ethan Kosco performed all experimental work, including viral production and injection, cell transfection, western blots, mouse sciatic nerve injury surgeries, muscle teasing, immunostaining, and confocal imaging under the supervision of Ivy Samuels. Hongyang Jing and Peng Chen contributed to viral production. The first draft of the manuscript was written by Ethan Kosco, and Lin Mei commented and revised it critically before final approval. Lin Mei Lin Mei and Ivy Samuels provided essential comments on figures created by Ethan Kosco. All authors read and approved the final manuscript.

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Correspondence to Lin Mei.

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Kosco, E.D., Jing, H., Chen, P. et al. DOK7 Promotes NMJ Regeneration After Nerve Injury. Mol Neurobiol 60, 1453–1464 (2023). https://doi.org/10.1007/s12035-022-03143-4

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