Sox10 and MRF: Interplay of two transcription factors as cornerstone of the regulatory network in myelinating oligodendrocytes
Developmental Neurobiology
Final Report Abstract
Only few transcriptional factors are known that are required for terminal differentiation of oligodendrocytes and myelination in the central nervous system. Sox10 and Myrf are two of them. In this project, we have shown that Sox10 induces Myrf expression in oligodendroglial cells shortly before the onset of differentiation. Induction is mediated by an oligodendrocytespecific enhancer in the first intron of the Myrf gene. Sox10 binds to this enhancer directly and requires the help of additional factors such as Olig2. Other regulators counteract Myrf induction. In case of Sox2, the mechanism appears to be posttranscriptional, and involves the Sox2-induced microRNA miR145. Once induced, Myrf cooperates with its inductor Sox10 and synergistically activates a large cohort of genes to kickstart the terminal differentiation program in oligodendrocytes. Among the jointly activated genes are many myelin genes, but also regulatory molecules such as the dual-specificity phosphatase Dusp15 that may integrate into the oligodendroglial regulatory network and contribute to its function. At least in case of Dusp15, synergism between Sox10 and Myrf appears to be mechanistically complex as it cannot be explained by protein-protein interactions between the factors and facilitated binding to adjacent sites in the responsible regulatory region. The identified Sox10-dependent positive feedforward loop involving Myrf is not only active during developmental myelination, but also during remyelination in the adult and may thus be relevant for Multiple Sclerosis. By the same mechanism, Sox10 is also able to induce Myrf expression in satellite glia of the peripheral nervous system and thereby convert these cells directly into myelinating oligodendrocytes in vivo. Our studies identify central functional interactions within the regulatory network that drives myelination in the central nervous system. They may also be helpful in delineating processes that are dysregulated or defective in central myelin diseases, and define starting points for the design of future therapeutic strategies.
Publications
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(2013) The transcription factors Sox10 and Myrf define an essential regulatory network module in differentiating oligodendrocytes. PLoS Genetics 9, e1003907
Hornig, J., Fröb, F., Vogl, M., Hermans-Borgmeyer, I., Tamm, E.R., Wegner, M.
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(2014) Stem cell factor Sox2 and its close relative Sox3 have differentiation functions in oligodendrocytes. Development 141, 39-50
Hoffmann, S.A., Hos, D., Küspert, M., Lang, R.A., Lovell-Badge, R., Wegner, M., Reiprich, S.
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(2015) Elevated in vivo levels of a single transcription factor directly convert satellite glia into oligodendrocyte-like cells. PLoS Genet. 11, e1005008
Weider, M., Wegener, A., Schmitt, C., Küspert, M., Hillgärtner, S., Bösl, M.R., Hermans- Borgmeyer, I., Nait-Oumesmar, B., Wegner, M.
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(2016) SomethiNG 2 talk about-Transcriptional regulation in embryonic and adult oligodendrocyte precursors. Brain Res. 1638, 167-182
Küspert, M., Wegner, M.
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(2016) The dual-specificity phosphatase Dusp15 is regulated by Sox10 and Myrf in myelinating oligodendrocytes. Glia 64, 2120–2132
Muth, K.N., Piefke, S., Weider, M., Sock, E., Hermans-Borgmeyer, I., Wegner, M., Küspert, M.
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(2017) Myelin Regulatory Factor 1 Drives Remyelination in Multiple Sclerosis. Acta Neuropathol. 134, 403–422
Duncan, G.J., Plemel, J.R., Assinck, P., Manesh, S.B., Muir, F.G.W., Hirata, R., Berson, M., Liu, J., Wegner, M., Emery, B., Moore, G.R.W., Tetzlaff, W.
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(2017) SoxE factors: Transcriptional regulators of neural differentiation and nervous system development. Semin Cell Dev Biol. 63, 35-42
Weider, M., Wegner, M.
