A genetic compensatory mechanism regulated by Jun and Mef2d modulates the expression of distinct class IIa Hdacs to ensure peripheral nerve myelination and repair

  1. Sergio Velasco-Aviles
  2. Nikiben Patel
  3. Angeles Casillas-Bajo
  4. Laura Frutos-Rincón
  5. Enrique Velasco-Serna
  6. Juana Gallar
  7. Peter Arthur-Farraj
  8. Jose A Gomez-Sanchez  Is a corresponding author
  9. Hugo Cabedo  Is a corresponding author
  1. Instituto de Neurociencias de Alicante UMH-CSIC, Spain
  2. University of Cambridge, United Kingdom

Abstract

The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express Hdac4, 5 and 7 but not Hdac9. Here we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when Hdac4 and 5 are knocked-out from Schwann cells in mice, a JUN-dependent mechanism induces the compensatory overexpression of Hdac7 permitting, although with a delay, the formation of the myelin sheath. When Hdac4,5 and 7 are simultaneously removed, the Myocyte-specific enhancer-factor d (MEF2D) binds to the promoter and induces the de novo expression of Hdac9, and although several melanocytic lineage genes are misexpressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa Hdac family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file

Article and author information

Author details

  1. Sergio Velasco-Aviles

    Instituto de Neurociencias de Alicante UMH-CSIC, Alicante, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Nikiben Patel

    Laboratorio 117, Instituto de Neurociencias de Alicante UMH-CSIC, San Juan, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0129-7622
  3. Angeles Casillas-Bajo

    Instituto de Neurociencias de Alicante UMH-CSIC, Alicante, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Laura Frutos-Rincón

    Instituto de Neurociencias de Alicante UMH-CSIC, Alicante, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Enrique Velasco-Serna

    Instituto de Neurociencias de Alicante UMH-CSIC, Alicante, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Juana Gallar

    Instituto de Neurociencias de Alicante UMH-CSIC, Alicante, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Peter Arthur-Farraj

    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1239-9392
  8. Jose A Gomez-Sanchez

    Instituto de Neurociencias de Alicante UMH-CSIC, Alicante, Spain
    For correspondence
    j.gomez@umh.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6746-1800
  9. Hugo Cabedo

    Instituto de Neurociencias de Alicante UMH-CSIC, Alicante, Spain
    For correspondence
    hugo.cabedo@umh.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1322-6290

Funding

Ministerio de Economía y Competitividad (BFU2016-75864R)

  • Hugo Cabedo

Ministerio de Economía y Competitividad (PID2019-109762RB-I00)

  • Hugo Cabedo

ISABIAL (UGP18-257)

  • Hugo Cabedo

ISABIAL (UGP-2019-128)

  • Hugo Cabedo

Conselleria de Cultura, Educación y Ciencia, Generalitat Valenciana (PROMETEO 2018/114)

  • Juana Gallar
  • Hugo Cabedo

Conselleria de Cultura, Educación y Ciencia, Generalitat Valenciana (ACIF/2 017/169)

  • Laura Frutos-Rincón

Ministerio de Educación, Cultura y Deporte (FPU16/00283)

  • Enrique Velasco-Serna

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 work was conducted according to European Union guidelines and with protocols approved by the Comité de Bioética y Bioseguridad del Instituto de Neurociencias de Alicante, Universidad Hernández de Elche and Consejo Superior de Investigaciones Científicas (http://in.umh.es/). Reference number for the aproved protocol: 2017/VSC/PEA/00022 tipo 2.

Reviewing Editor

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

Publication history

  1. Received: August 9, 2021
  2. Preprint posted: September 21, 2021 (view preprint)
  3. Accepted: January 24, 2022
  4. Accepted Manuscript published: January 25, 2022 (version 1)
  5. Version of Record published: February 17, 2022 (version 2)
  6. Version of Record updated: November 14, 2022 (version 3)

Copyright

© 2022, Velasco-Aviles 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. Sergio Velasco-Aviles
  2. Nikiben Patel
  3. Angeles Casillas-Bajo
  4. Laura Frutos-Rincón
  5. Enrique Velasco-Serna
  6. Juana Gallar
  7. Peter Arthur-Farraj
  8. Jose A Gomez-Sanchez
  9. Hugo Cabedo
(2022)
A genetic compensatory mechanism regulated by Jun and Mef2d modulates the expression of distinct class IIa Hdacs to ensure peripheral nerve myelination and repair
eLife 11:e72917.
https://doi.org/10.7554/eLife.72917