Control of Nervous System Maintenance and Regeneration by Chromatin Remodeling Enzymes
Our group investigates how chromatin-remodeling enzymes including histone deacetylases (HDACs) and demethylases (HDMs) control the maintenance and regeneration of the nervous system after an injury. Our work is focused on the functions of myelinating cells, Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system, in these processes.
HDACs and HDMs are key epigenetic regulators that modify chromatin architecture by deacetylating and demethylating histones, respectively. In addition, HDACs deacetylate and thereby modulate the activity of many transcription factors. These enzymes are thus very powerful transcriptional regulators controlling gene activity at different levels.
We have shown that HDAC1 and HDAC2, two members of the class I HDACs, control the development of Schwann cells, from specification (Jacob et al., J. Neurosci., 2014) to terminal differentiation (Jacob et al., Nat. Neurosci., 2011). The work of our group is now focused on the functions of chromatin remodeling enzymes in the maintenance and regeneration of the nervous system. We showed that HDAC1 and HDAC2 are necessary to maintain the integrity of the PNS in adults (Brügger et al., PLOS Biol, 2015), and that they slow down axonal regeneration after lesion but are required for remyelination of regenerated axons (Brügger et al., Nat. Comm., 2017).
The PNS can efficiently regenerate after a lesion, whereas regeneration in the CNS is not efficient. This is in large part due to the presence of different types of glial cells in these two systems. Indeed, Schwann cells in the PNS promote axonal regeneration after lesion, whereas oligodendrocytes in the CNS and the formation of a glial scar prevent axonal regrowth. Our group compares the essential functions of chromatin-remodeling enzymes in Schwann cells and oligodendrocytes to better understand how Schwann cells promote axonal regeneration and to use this new knowledge to induce regeneration in the CNS. For this work, we have set up an innovative lesion model using microfluidics. With this model, we identified a previously unknown behavior of Schwann cells that occurs early after an axonal lesion: we showed that Schwann cells build actin spheres to induce the disintegration of the damaged part of the axons after lesion, which accelerates the regrowth of the surviving axons. By elucidating the mechanism of action underlying this behavior, we were able to transfer this behavior in oligodendrocytes, which promoted axonal regrowth after lesion (Vaquié et al., Cell Reports, 2019).
We are continuing to use our lesion models to identify other potential mechanisms that could increase the plasticity of the PNS and CNS. We use these discoveries to test exploratory treatments in mouse models to improve the maintenance of integrity of the nervous system in young and old adults and its regeneration after injury. The aims of our work are thus to unravel basic mechanisms of cell plasticity and help in designing novel therapeutic strategies for neurodegenerative diseases and regeneration of the nervous system after injury.
To reach our aims, We combine a wide range of in vivo and in vitro approaches: we use mouse genetics, behavioral analyses, molecular and cellular biology, viral vectors, classic and advanced imaging techniques including high-resolution live-cell imaging at the single-cell level and 4D reconstruction, biochemistry, proteomics, transcriptomics, and epigenomics.