Functions of HDAC8 in Schwann cells during development, maintenance and regeneration of the peripheral nervous system

• Applicant: Professorin Dr. Claire Jacob
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459819328

Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), react to a PNS injury by converting into repair cells that foster axonal regrowth, and then remyelinate or re-ensheath regenerated axons, thereby ensuring functional recovery. The efficiency of this mechanism depends however on the time needed for axons to regrow. In the first funding period of this grant, we have shown that ablation of histone deacetylase 8 (HDAC8) in SCs accelerates the regrowth of sensory axons and sensory function recovery. We found that HDAC8 is specifically expressed in sensory SCs and regulates the E3 ubiquitin ligase TRAF7, which destabilizes hypoxia-inducible factor 1-alpha (HIF1) and counteracts the phosphorylation and upregulation of c-Jun, a major inducer of the repair SC phenotype. Our study indicates that this phenotype switch is regulated by different mechanisms in sensory and motor SCs and is accelerated by HDAC8 downregulation, which promotes sensory axon regeneration and sensory function recovery. This work raises several questions that we would like to answer in the new funding period: When does HDAC8 expression begin to be restricted to SCs that envelop sensory axons, and what causes SCs to express or downregulate HDAC8? Does HDAC8 remain expressed in SCs associated with sensory axons after injury? By what mechanism does HDAC8 regulate TRAF7 expression? Our further work on this project shows that HDAC8 interacts with another key factor and that TRAF7 regulates its expression. We want to understand whether HDAC8, TRAF7 and this newly identified factor form a single protein complex or, instead, two different complexes with two different functions. Since this factor is an important regulator of homeostasis, does the loss of HDAC8 lead to a maintenance phenotype in adult peripheral nerves?

• DFG Programme: Research Grants