A genetic compensatory mechanism regulated by Jun and Mef2d modulates the expression of distinct class IIa Hdacs to ensure peripheral nerve myelination and repair
- Instituto de Neurociencias de Alicante UMH-CSIC, Spain
- 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
Peter Arthur-Farraj
Jose A Gomez-Sanchez
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.
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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
