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
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459819328

Chromatin-remodeling enzymes of the histone deacetylase (HDAC) family are key transcriptional regulators, which can control transcriptional activity by deacetylating histones and also by deacetylating non-histone targets such as transcription factors.We have previously shown that the two members of the HDAC family HDAC1 and HDAC2 (HDAC1/2) play a key role in Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), during PNS development, maintenance and regeneration after lesion. Other groups have also shown additional functions for HDAC3 and HDAC4 in SC myelination, de-differentiation and remyelination after lesion.In vertebrates, axons of the PNS interact with SCs. These interactions are critical to protect axons from the external environment and prevent their degradation. In addition, myelin built by SCs is essential for axonal insulation and for fast conduction of electric signals along axons. Indeed, myelin disorders can occur in various cases in humans and can lead to severe disabilities. For instance, a large group of inherited peripheral neuropathies called Charcot-Marie-Tooth disease leads to PNS demyelination and/or axonal degeneration. PNS demyelination can also be secondary to an infection (e.g. Guillain-Barré syndrome), to diabetes, toxic agents, aging, or to a traumatic lesion.Understanding the mechanisms that control SC development, maintenance in adults and plasticity after lesion is of potential major importance to elaborate new therapies for the improvement of PNS repair. In addition, this knowledge can constitute a basis for the comparison of regulations between SCs and oligodendrocytes (OLs), the myelinating glia of the central nervous system, and help identifying potential critical differences explaining why SCs can promote axonal regeneration whereas OLs cannot.We found that HDAC8, another member of the HDAC family, is robustly expressed and regulated in SCs during development and regeneration after a PNS lesion. The functions of HDAC8 in these processes have however not been reported so far. In this project, we will elucidate the functions of HDAC8 in SCs during PNS development, in the maintenance of PNS integrity in adults and in the regeneration process of the PNS after lesion. Depending on these results, we will test whether increasing or decreasing HDAC8 activity in vivo enhances regeneration efficiency after lesion in young adults where the regeneration process is efficient and in aged mice where regeneration efficiency declines.

• DFG Programme: Research Grants