1. Neuroscience
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A mechanism in Agrin signaling revealed by a prevalent Rapsyn mutation in congenital myasthenic syndrome

  1. Guanglin Xing
  2. Hongyang Jing
  3. Lei Zhang
  4. Yu Cao
  5. Lei Li
  6. Kai Zhao
  7. Zhaoqi Dong
  8. Wenbing Chen
  9. Hongsheng Wang
  10. Rangjuan Cao
  11. Wen-Cheng Xiong
  12. Lin Mei  Is a corresponding author
  1. Case Western Reserve University, United States
  2. Augusta University, United States
Research Article
  • Cited 8
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Cite this article as: eLife 2019;8:e49180 doi: 10.7554/eLife.49180

Abstract

Neuromuscular junction is a synapse between motoneurons and skeletal muscles, where acetylcholine receptors (AChRs) are concentrated to control muscle contraction. Studies of this synapse have contributed to our understanding of synapse assembly and pathological mechanisms of neuromuscular disorders. Nevertheless, underlying mechanisms of NMJ formation was not well understood. To this end, we took a novel approach - studying mutant genes implicated in congenital myasthenic syndrome (CMS). We showed that knock-in mice carrying N88K, a prevalent CMS mutation of Rapsyn (Rapsn), died soon after birth with profound NMJ deficits. Rapsn is an adapter protein that bridges AChRs to the cytoskeleton and possesses E3 ligase activity. In investigating how N88K impairs the NMJ, we uncovered a novel signaling pathway by which Agrin-LRP4-MuSK induces tyrosine phosphorylation of Rapsn, which is required for its self-association and E3 ligase activity. Our results also provide insight into pathological mechanisms of CMS.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data about statistical results are provided in excel files, including Figures 1E-J, 2E-H, 2M, 2N, 3A, 3B, 3D, 3E, 4B, 4F, 5D, 5F, 5H, 6D, 6G, 6I, 7B, 7F, 7H, 7J, 7L, 7N, 8B, 8C, 8D, ; Figure 1-figure supplement 1C, 1E, 1H, Figure 4-figure supplement 1B, Figure 4-figure supplement 2B and 2D, Figure 5-figure supplement 1D, Figure 7-figure supplement 1C and E.

Article and author information

Author details

  1. Guanglin Xing

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Hongyang Jing

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Lei Zhang

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yu Cao

    Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3708-575X
  5. Lei Li

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kai Zhao

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhaoqi Dong

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Wenbing Chen

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Hongsheng Wang

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Rangjuan Cao

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Wen-Cheng Xiong

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Lin Mei

    Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States
    For correspondence
    lin.mei@case.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5772-1229

Funding

NIH Blueprint for Neuroscience Research (RES220572)

  • 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: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (2017-0115) of the University of Case Western Reserve University. Animal protocols have been approved by the Institutional Animal Care and Use Committee of Case Western Reserve University.

Reviewing Editor

  1. Gary L Westbrook, Oregon Health and Science University, United States

Publication history

  1. Received: June 9, 2019
  2. Accepted: September 23, 2019
  3. Accepted Manuscript published: September 24, 2019 (version 1)
  4. Version of Record published: October 7, 2019 (version 2)

Copyright

© 2019, Xing 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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