Functions of histone deacetylase 8 in schwann cells during peripheral nervous system regeneration

Abstract

In contrast to the central nervous system, the peripheral nervous system (PNS) has an amazing regenerative capacity after lesion. Indeed, Schwann cells (SCs), the PNS myelinating glial cells, are highly plastic and react to injury by demyelinating and converting into repair cells that foster axonal regrowth, guide axons back to their former target, and then remyelinate the regenerated axons. The conversion into repair SCs is largely controlled by the transcription factor c-Jun. However, the mechanisms that induce c-Jun upregulation after injury are partially understood. In our study, we show that ablating histone deacetylase 8 (HDAC8) in adult SCs enhances c-Jun phosphorylation and upregulation early after lesion and accelerates the regrowth of sensory axons and sensory function recovery. After lesion, the interruption of oxygen supply creates a hypoxic environment, which is known to upregulate c-Jun phosphorylation and expression and is characterized by hypoxia-inducible-factor 1⍺ (HIF1⍺) upregulation. Additionally, we found that HDAC8 stabilizes the E3 ubiquitin ligase TRAF7, which destabilizes HIF1⍺, resulting in a delayed conversion into repair SCs. Our study emphasizes the function of HIF1⍺ in SCs after injury and demonstrates that downregulating HDAC8 improves SC plasticity and promotes sensory axons regeneration and functional recovery by stabilizing HIF1⍺. Interestingly, we found that HDAC8 ablation specifically promotes the regrowth of sensory axons and sensory function recovery and that HDAC8 is detected only in SCs ensheating sensory axons. This indicates that a specific subtype of SCs ensheating only sensory axons can be identified using HDAC8 as a marker and that the conversion of SCs into repair SCs is controlled by different mechanisms in motor and sensory SCs.