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.
Highlights
44 45 During the postnatal development of the peripheral nervous system (PNS), immature Schwann cells ensheath large caliber axons of sensory and motor neurons and differentiate, forming myelin, a highly specialized plasma membrane that increases nerve impulse velocity by allowing saltatory conduction
We have previously shown that Hdac4 and Hdac5 redundantly contribute to activate the myelin transcriptional program in Schwann cells in vivo
We found three peaks of HDAC4 bound near the TSS of Pou3f1 (Figures 7B and 7G), a result that was confirmed by Chromatin immunoprecipitation assays (ChIP)-qPCR (Figure 7H). Regarding the melanocyte lineage, we found a clear peak of HDAC4 close the TSS of Mcam (Figure 7B), we did not detect peaks in Tyrosinase-related protein 1 encoding gene (Tyrp1) and Ednrb, suggesting that, while HDAC4 directly represses the expression of Mcam it likely indirectly leads to Tyrp1 and Ednrb repression
Summary
2 by Jun and Mef2d modulates the expression of 3 distinct class IIa Hdacs to ensure peripheral. 10 1Instituto de Neurociencias de Alicante UMH-CSIC, San Juan de Alicante 03550, Spain. 11 2Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante 03010, Spain. 12 3The European University of Brain and Technology-NeurotechEU, San Juan de Alicante 03550, Spain. 15 *These authors contributed to this work
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