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

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.

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.

Metrics

  • 1,638
    views
  • 250
    downloads
  • 9
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.72917

Further reading

    1. Cell Biology
    Kaili Du, Hongyu Chen ... Dan Li
    Research Article

    Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

    1. Cell Biology
    2. Developmental Biology
    Sarah Y Coomson, Salil A Lachke
    Insight

    A study in mice reveals key interactions between proteins involved in fibroblast growth factor signaling and how they contribute to distinct stages of eye lens development.