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Motoneuron Wnts regulate neuromuscular junction development

  1. Chengyong Shen  Is a corresponding author
  2. Lei Li
  3. Kai Zhao
  4. Lei Bai
  5. Ailian Wang
  6. Xiaoqiu Shu
  7. Yatao Xiao
  8. Jianmin Zhang
  9. Kejing Zhang
  10. Tiankun Hui
  11. Wenbing Chen
  12. Bin Zhang
  13. Wei Hsu
  14. Wen-Cheng Xiong
  15. Lin Mei  Is a corresponding author
  1. Zhejiang University, China
  2. Case Western Reserve University, United States
  3. Augusta University, United States
  4. Nanchang University, China
  5. Huazhong University of Science and Technologyy, China
  6. University of Rochester Medical Center, United States
Research Article
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Cite this article as: eLife 2018;7:e34625 doi: 10.7554/eLife.34625

Abstract

The neuromuscular junction (NMJ) is a synapse between motoneurons and skeletal muscles to control motor behavior. Unlike extensively investigated postsynaptic differentiation, less is known about mechanisms of presynaptic assembly. Genetic evidence of Wnt in mammalian NMJ development was missing due to the existence of multiple Wnts and their receptors. We show when Wnt secretion is abolished from motoneurons by mutating the Wnt ligand secretion mediator (Wls) gene, mutant mice showed muscle weakness and neurotransmission impairment. NMJs were unstable with reduced synaptic junctional folds and fragmented AChR clusters. Nerve terminals were swollen; synaptic vesicles were fewer and mislocated. The presynaptic deficits occurred earlier than postsynaptic deficits. Intriguingly, these phenotypes were not observed when deleting Wls in muscles or Schwann cells. We identified Wnt7A and Wnt7B as major Wnts for nerve terminal development in rescue experiments. These observations demonstrate a necessary role of motoneuron Wnts in NMJ development, in particular presynaptic differentiation.

Article and author information

Author details

  1. Chengyong Shen

    Institute of Translational Medicine, Zhejiang University, Hangzhou, China
    For correspondence
    cshen@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  2. Lei Li

    Department of Neuroscience, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kai Zhao

    Department of Neuroscience and Regenerative Medicine, Augusta University, Georgia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Lei Bai

    Institute of Translational Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Ailian Wang

    Institute of Translational Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Xiaoqiu Shu

    Institute of Translational Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yatao Xiao

    Institute of Translational Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Jianmin Zhang

    Institute of Translational Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Kejing Zhang

    Institute of Translational Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Tiankun Hui

    Institute of Life Science, Nanchang University, Jiangxi, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Wenbing Chen

    Department of Neuroscience, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Bin Zhang

    Department of Physiology, Huazhong University of Science and Technologyy, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Wei Hsu

    Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Wen-Cheng Xiong

    Department of Neuroscience, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9071-7598
  15. Lin Mei

    Department of Neuroscience, Case Western Reserve University, Cleveland, United States
    For correspondence
    lin.mei@case.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National key research and development program of china (2017YFA0104903)

  • Chengyong Shen

Zhejiang provincial Natural Sciences Foundation of China (LR17H090001)

  • Chengyong Shen

National Natural Science Foundation of China (31671040)

  • Chengyong Shen

National Natural Science Foundation of China (31701036)

  • Kejing Zhang

National Institutes of Health

  • Lin Mei

National Institutes of Health

  • Wen-Cheng Xiong

Muscular Dystrophy Association

  • Lin Mei

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments with animals were approved by Institutional Animal Care andUse Committees of Augusta University (2011-0393), Case Western Reserve University (2017-0115), and Zhejiang University (10262).

Reviewing Editor

  1. Jeremy Nathans, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: December 27, 2017
  2. Accepted: August 9, 2018
  3. Accepted Manuscript published: August 16, 2018 (version 1)
  4. Version of Record published: September 7, 2018 (version 2)

Copyright

© 2018, Shen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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