Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking
- Albert Einstein College of Medicine, United States
- Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, China
- Children's National Hospital, United States
- Brown University, United States
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.
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Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde traffickingDryad Digital Repository, doi:10.5061/dryad.vmcvdncwt.
Article and author information
Author details
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.
Reviewing Editor
- Kassandra M Ori-McKenney, University of California, United States
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).
Version history
- Received: July 27, 2022
- Preprint posted: August 11, 2022 (view preprint)
- Accepted: December 6, 2022
- Accepted Manuscript published: December 7, 2022 (version 1)
- Accepted Manuscript updated: December 12, 2022 (version 2)
- Version of Record published: December 29, 2022 (version 3)
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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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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