Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation
- Sorbonne Université, Inserm U1127, CNRS UMR 7225, France
- University of California, Davis, United States
- 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
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Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiationNCBI Gene Expression Omnibus, GSE203295.
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scRNA-seq postnatal oligodendrogliaNCBI Gene Expression Omnibus, GSE75330.
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scRNA-seq developmental oligodendrogliaNCBI Gene Expression Omnibus, GSE95194.
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scRNA-seq from iPSC-derived Human Oligodendrocyte Progenitor CellsNCBI Gene Expression Omnibus,GSE146373.
Article and author information
Author details
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
- Klaus-Armin Nave, Max Planck Institute of Experimental Medicine, Germany
Version history
- Preprint posted: February 27, 2022 (view preprint)
- Received: May 15, 2022
- Accepted: June 27, 2022
- Accepted Manuscript published: October 10, 2022 (version 1)
- 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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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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