Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation

  1. Emeric Merour
  2. Hatem Hmidan
  3. Corentine Marie
  4. Pierre-Henri Helou
  5. Haiyang Lu
  6. Antoine Potel
  7. Jean-Baptiste Hure
  8. Adrien Clavairoly
  9. Yi Ping Shih
  10. Salman Goudarzi
  11. Sebastien Dussaud
  12. philippe Ravassard
  13. Sassan Hafizi
  14. Su Hao Lo
  15. Bassem A Hassan
  16. Carlos Parras  Is a corresponding author
  1. Sorbonne Université, Inserm U1127, CNRS UMR 7225, France
  2. University of California, Davis, United States
  3. University of Portsmouth, United Kingdom

Abstract

The differentiation of oligodendroglia from oligodendrocyte precursor cells (OPCs) to complex and extensive myelinating oligodendrocytes (OLs) is a multistep process that involves largescale morphological changes with significant strain on the cytoskeleton. While key chromatin and transcriptional regulators of differentiation have been identified, their target genes responsible for the morphological changes occurring during OL myelination are still largely unknown. Here, we show that the regulator of focal adhesion, Tensin3 (Tns3), is a direct target gene of Olig2, Chd7, and Chd8, transcriptional regulators of OL differentiation. Tns3 is transiently upregulated and localized to cell processes of immature OLs, together with integrin-b1, a key mediator of survival at this transient stage. Constitutive Tns3 loss-of-function leads to reduced viability in mouse and humans, with surviving knockout mice still expressing Tns3 in oligodendroglia. Acute deletion of Tns3 in vivo, either in postnatal neural stem cells (NSCs) or in OPCs, leads to a two-fold reduction in OL numbers. We find that the transient upregulation of Tns3 is required to protect differentiating OPCs and immature OLs from cell death by preventing the upregulation of p53, a key regulator of apoptosis. Altogether, our findings reveal a specific time window during which transcriptional upregulation of Tns3 in immature OLs is required for OL differentiation likely by mediating integrin-b1 survival signaling to the actin cytoskeleton as OL undergo the large morphological changes required for their terminal differentiation.

Data availability

Sequencing data have been deposited in GEO under accession code GSE203295

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Emeric Merour

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Hatem Hmidan

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Corentine Marie

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Pierre-Henri Helou

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Haiyang Lu

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Antoine Potel

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Jean-Baptiste Hure

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Adrien Clavairoly

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Yi Ping Shih

    Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Salman Goudarzi

    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Sebastien Dussaud

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5365-8338
  12. philippe Ravassard

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Sassan Hafizi

    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4539-0888
  14. Su Hao Lo

    Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2675-9387
  15. Bassem A Hassan

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9533-4908
  16. Carlos Parras

    Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Paris, France
    For correspondence
    carlos.parras@icm-institute.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0248-1752

Funding

National Multiple Sclerosis Society (NMSS RG-1501-02851)

  • Carlos Parras

Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques (ARSEP 2014,2015,2018,2019,2020)

  • Corentine Marie

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 performed according to the guidelines and regulations of the Inserm ethical committees (authorization #A75-13-19) and animal experimentation license A75-17-72

Reviewing Editor

  1. Klaus-Armin Nave, Max Planck Institute of Experimental Medicine, Germany

Publication history

  1. Preprint posted: February 27, 2022 (view preprint)
  2. Received: May 15, 2022
  3. Accepted: June 27, 2022
  4. Accepted Manuscript published: October 10, 2022 (version 1)
  5. Version of Record published: October 25, 2022 (version 2)

Copyright

© 2022, Merour 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. Emeric Merour
  2. Hatem Hmidan
  3. Corentine Marie
  4. Pierre-Henri Helou
  5. Haiyang Lu
  6. Antoine Potel
  7. Jean-Baptiste Hure
  8. Adrien Clavairoly
  9. Yi Ping Shih
  10. Salman Goudarzi
  11. Sebastien Dussaud
  12. philippe Ravassard
  13. Sassan Hafizi
  14. Su Hao Lo
  15. Bassem A Hassan
  16. Carlos Parras
(2022)
Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation
eLife 11:e80273.
https://doi.org/10.7554/eLife.80273

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