Abhängigkeit der Gliazell-Entwicklung von Dimerisierung und zellspezifischer Transaktivierung des Transkriptionsfaktors Sox10
Final Report Abstract
The transcription factor Sox10 is a central developmental and homeostatic regulator in Schwann cells of the peripheral and oligodendrocytes of the central nervous system. During development of these cells, Sox10 is especially important for terminal differentiation and required for the production of myelin which allows rapid saltatory conduction in the nervous system of all vertebrates, including humans. While it has become clear over the years how Sox10 induces and interacts with other transcription factors in myelinating glia, little is known about its relationship to chromatin-changing and transcription-influencing complexes. In this project, we have shown that Sox10 recruits chromatin remodeling complexes, transcriptioninitiating and transcription-elongating complexes to perform its function in the nucleus of a glial cell by physically interacting with specific subunits of these complexes via several of its protein domains. The BAF complex is recruited by interaction with Baf60a, the Mediator complex by interaction with Med12, and the P-TEFb elongation factor by interaction with cyclin T1. Intriguingly, some of the complexes are of similar functional importance in both types of myelinating glia such as the Mediator complex. Others are much more important in one cell type than in the other, such as the BAF complex which is essential for Sox10-dependent terminal differentiation of Schwann cells, but not for Sox10-dependent terminal differentiation of oligodendrocytes. These studies reveal the complex network of interactions that a central regulator of myelination has to sustain to perform its function. They unravel the underlying processes of myelination and as a consequence may be helpful in understanding dysregulations and defects that give rise to or are at work during myelin diseases including multiple sclerosis and a vast array of peripheral neuropathies.
Publications
- (2012) Chromatin remodelling factor Brg1 is required for Schwann cell differentiation and myelination. Dev. Cell 23, 193-201
Weider, M., Küspert, M., Bischof, M., Vogl, M.R., Hornig, J., Loy, K., Kosian, T., Müller, J., Hillgärtner, S., Tamm, E.R., Metzger, D., Wegner, M.
(See online at https://doi.org/10.1016/j.devcel.2012.05.017) - (2013) Mighty Bugs: Leprosy Bacteria Turn Schwann Cells into Stem Cells. Cell 152, 15-16
Wegner, M.
- (2013) Sox appeal – Sox10 attracts epigenetic and transcriptional regulators in myelinating glia. Biol. Chem. 394, 1583-1593
Weider, M., Reiprich, S., Wegner, M.
- (2013) Sox10 cooperates with the Mediator subunit 12 during terminal differentiation of myelinating glia. J. Neurosci. 33, 6679-6690
Vogl, M.R., Reiprich, R., Küspert, M., Kosian, T., Schrewe, H., Nave, K.-A., Wegner, M.
(See online at https://doi.org/10.1523/JNEUROSCI.5178-12.2013) - (2015) Brg1-dependent chromatin remodelling is not essentially required during oligodendroglial differentiation. J. Neurosci. 35, 21-35
Bischof, M., Weider, M., Küspert, M., Nave, K.-A., Wegner, M.
(See online at https://doi.org/10.1523/JNEUROSCI.1468-14.2015) - (2015) From CNS stem cells to neurons and glia: Sox for everyone. Cell Tissue Res. 359, 111-124
Reiprich, S., Wegner, M.
(See online at https://doi.org/10.1007/s00441-014-1909-6) - (2015) Transcription factors Sox10 and Sox2 functionally interact with positive transcription elongation factor b in Schwann cells. J. Neurochem. 132, 384-393
Arter, J., Wegner, M.
(See online at https://doi.org/10.1111/jnc.13013) - (2016) Schwann cells and their transcriptional network: Evolution of key regulators of peripheral myelination. Brain Res.
Stolt, C.C., Wegner, M.
(See online at https://doi.org/10.1016/j.brainres.2015.09.025)
