1. Neuroscience
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DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction

  1. Eva On-Chai Lau
  2. Devid Damiani
  3. Georges Chehade
  4. Nuria Ruiz-Reig
  5. Rana Saade
  6. Yves Jossin
  7. Mohamed Aittaleb
  8. Olivier Schakman
  9. Nicolas Tajeddine
  10. Philippe Gailly
  11. Fadel Tissir  Is a corresponding author
  1. Université catholique de Louvain, Belgium
  2. Université Catholique de Louvain, Belgium
  3. HBKU, Qatar
Research Article
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Cite this article as: eLife 2021;10:e61974 doi: 10.7554/eLife.61974

Abstract

Diaphanous (DIAPH) 3 is a member of the formin proteins that have the capacity to nucleate and elongate actin filaments and therefore, to remodel the cytoskeleton. DIAPH3 is essential for cytokinesis as its dysfunction impairs the contractile ring and produces multinucleated cells. Here, we report that DIAPH3 localizes at the centrosome during mitosis and regulates the assembly and bi-polarity of the mitotic spindle. DIAPH3-deficient cells display disorganized cytoskeleton, and multipolar spindles. DIAPH3-deficiency disrupts the expression and/or stability of several proteins including the kinetochore-associated protein SPAG5. DIAPH3 and SPAG5 have similar expression patterns in the developing brain and overlapping subcellular localization during mitosis. Knockdown of SPAG5 phenocopies the DIAPH3 deficiency, whereas its overexpression rescues the DIAHP3 knockdown phenotype. Conditional inactivation of Diaph3 in mouse cerebral cortex profoundly disrupts neurogenesis depleting cortical progenitors and neurons; and leading to cortical malformation and autistic-like behavior. Our data uncover uncharacterized functions of DIAPH3 and provide evidence that this protein belongs to a molecular toolbox that links microtubule dynamics during mitosis to aneuploidy, cell death, fate determination defects, and cortical malformation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures

Article and author information

Author details

  1. Eva On-Chai Lau

    Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
    Competing interests
    No competing interests declared.
  2. Devid Damiani

    Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
    Competing interests
    No competing interests declared.
  3. Georges Chehade

    Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
    Competing interests
    No competing interests declared.
  4. Nuria Ruiz-Reig

    Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
    Competing interests
    No competing interests declared.
  5. Rana Saade

    Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
    Competing interests
    No competing interests declared.
  6. Yves Jossin

    Laboratory of Mammalian Development and Cell Biology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8466-7432
  7. Mohamed Aittaleb

    College of Health and Life Sciences, HBKU, Doha, Qatar
    Competing interests
    No competing interests declared.
  8. Olivier Schakman

    Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
    Competing interests
    No competing interests declared.
  9. Nicolas Tajeddine

    Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
    Competing interests
    No competing interests declared.
  10. Philippe Gailly

    Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
    Competing interests
    No competing interests declared.
  11. Fadel Tissir

    Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium
    For correspondence
    fadel.tissir@uclouvain.be
    Competing interests
    Fadel Tissir, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9292-6622

Funding

Fonds De La Recherche Scientifique - FNRS (FNRS PDR T00075.15)

  • Fadel Tissir

Fonds De La Recherche Scientifique - FNRS (FNRS PDR T0236.20)

  • Fadel Tissir

Fonds De La Recherche Scientifique - FNRS (EOS 30913351)

  • Fadel Tissir

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 carried out in accordance with European guidelines and approved by the animal ethics committee of the Université Catholique de Louvain (permit number 2019/UCL/MD/006

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Publication history

  1. Received: August 10, 2020
  2. Accepted: April 23, 2021
  3. Accepted Manuscript published: April 26, 2021 (version 1)
  4. Version of Record published: May 6, 2021 (version 2)

Copyright

© 2021, Lau 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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