1. Cell Biology

Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking

  1. Lu Rao
  2. Peijun Li
  3. Xinglei Liu
  4. Qi Wang
  5. Alexander I Son
  6. Arne Gennerich  Is a corresponding author
  7. Judy Shih-Hwa Liu  Is a corresponding author
  8. Xiaoqin Fu  Is a corresponding author
  1. Albert Einstein College of Medicine, United States
  2. Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, China
  3. Brown University, United States
  4. Children's National Hospital, United States
https://doi.org/10.7554/eLife.82218
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Cite this article
  1. Lu Rao
  2. Peijun Li
  3. Xinglei Liu
  4. Qi Wang
  5. Alexander I Son
  6. Arne Gennerich
  7. Judy Shih-Hwa Liu
  8. Xiaoqin Fu
(2022)
Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking
eLife 11:e82218.
https://doi.org/10.7554/eLife.82218
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Abstract

Mutations in the microtubule (MT)-binding protein doublecortin (DCX) or in the MT-based molecular motor dynein result in lissencephaly. However, a functional link between DCX and dynein has not been defined. Here, we demonstrate that DCX negatively regulates dynein-mediated retrograde transport in neurons from Dcx-/y or Dcx-/y;Dclk1-/- mice by reducing dynein's association with MTs and by disrupting the composition of the dynein motor complex. Previous work showed an increased binding of the adaptor protein C-Jun-amino-terminal kinase-interacting protein 3 (JIP3) to dynein in the absence of DCX. Using purified components, we demonstrate that JIP3 forms an active motor complex with dynein and its cofactor dynactin with two dyneins per complex. DCX competes with the binding of the second dynein, resulting in a velocity reduction of the complex. We conclude that DCX negatively regulates dynein-mediated retrograde transport through two critical interactions by regulating dynein binding to MTs and by regulating the composition of the dynein motor complex.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for figure 2, 3, 4, figure 2-figure supplement 1 and table 1.

The following data sets were generated

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Author details

  1. Lu Rao

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Peijun Li

    Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Xinglei Liu

    Department of Neurology, Brown University, Providence, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Qi Wang

    Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Alexander I Son

    Children's National Research Institute, Children's National Hospital, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Arne Gennerich

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, United States
    For correspondence
    arne.gennerich@einsteinmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8346-5473

  7. Judy Shih-Hwa Liu

    Department of Neurology, Brown University, Providence, United States
    For correspondence
    judy_liu@brown.edu
    Competing interests
    The authors declare that no competing interests exist.

  8. Xiaoqin Fu

    Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
    For correspondence
    fuxq@wzhealth.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6354-8960

Funding

National Natural Science Foundation of China (81971425)

  • Xiaoqin Fu

National Natural Science Foundation of China (81871035)

  • Peijun Li

Natural Science Foundation of Zhejiang Province (LZ09H090001)

  • Peijun Li

Natural Science Foundation of Zhejiang Province (LY20H040002)

  • Xiaoqin Fu

National Institutes of Health (R01GM098469)

  • Arne Gennerich

National Institutes of Health (R01NS114636)

  • Arne Gennerich

National Institutes of Health (RO1NS104428-01)

  • Judy Shih-Hwa Liu

Brain and Behavior Research Foundation

  • Judy Shih-Hwa Liu

Whitehall Foundation

  • Judy Shih-Hwa Liu

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

Ethics

Animal experimentation: All animal procedures were approved by the Committee on the Ethics of Animal Experiments of Wenzhou Medical University (Permit number: wydw2019-0723).

Copyright

© 2022, Rao 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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  1. Lu Rao
  2. Peijun Li
  3. Xinglei Liu
  4. Qi Wang
  5. Alexander I Son
  6. Arne Gennerich
  7. Judy Shih-Hwa Liu
  8. Xiaoqin Fu
(2022)
Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking
eLife 11:e82218.
https://doi.org/10.7554/eLife.82218

Share this article

https://doi.org/10.7554/eLife.82218

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