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

• Published in: eLife 2022-01, Vol.11
• Main Authors: Velasco-Aviles, Sergio, Patel, Nikiben, Casillas-Bajo, Angeles, Frutos-Rincón, Laura, Velasco, Enrique, Gallar, Juana, Arthur-Farraj, Peter, Gomez-Sanchez, Jose A, Cabedo, Hugo
• Format: Article
• Language: English
• Subjects: Animals; Cell Biology; class II HDACs; Female; gene compensation; Gene expression; Gene Expression Regulation - physiology; Genes, jun - genetics; Genetic aspects; Genetic transcription; Genotype & phenotype; Histone deacetylase; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones; Male; MEF2 Transcription Factors - genetics; MEF2 Transcription Factors - metabolism; Mice; Morphology; myelin; Myelination; Myocytes; nerve development; nerve regeneration; Neuroscience; Peripheral nerves; Peripheral Nerves - physiology; Proteins; Remyelination; Schwann cells; Schwann Cells - metabolism; Scientific equipment and supplies industry; Transcription factors
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.72917

The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express , , and but not . 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 and are knocked-out from Schwann cells in mice, a JUN-dependent mechanism induces the compensatory overexpression of permitting, although with a delay, the formation of the myelin sheath. When , , and are simultaneously removed, the myocyte-specific enhancer-factor d (MEF2D) binds to the promoter and induces the de novo expression of , 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 family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.