Die Rolle von microRNAs im Gen-regulatorischen Netzwerk oligodendroglialer Zellen
Zusammenfassung der Projektergebnisse
The development of myelinating oligodendrocytes is tightly controlled at all stages from specification through differentiation to myelination. With this work we emphasize on the fact that transcription factors as the classical regulators of gene expression maintain numerous interactions with microRNAs, which can multiply and fine-regulate the transcription factors' effects. The functions of Sox10 as a central regulator in oligodendroglia are diversified by downstream acting microRNAs. This helps to explain some of the effects of Sox10 that were not understood before. Sox10 is expressed as soon as oligodendrocyte precursor cells arise from the neuroepithelium, while most of its direct target genes are only expressed in late developmental stages with the onset of terminal differentiation. Now, we show that microRNAs are further essential target genes of Sox10 and describe some of their Sox10- responsive regulatory elements in detail. Sox10 activates miR-338 and miR-335, which inhibit the expression of Sox9. This gives Sox10 indirect inhibitor functions, which are necessary to switch to the stage of terminal differentiation. A comparable mode of interaction applies to Tcf7l2, whose expression is finally contained by the Sox10-dependent microRNAs miR-338 and miR-155. Here, Sox10 can accomplish a transient expression pattern by first directly activating Tcf7l2 and then indirectly repressing it via delayed microRNA-mediated inhibition. With our collaboration partners, we established a publicly available network analysis tool to predict more of such interactions for further research. We established Sox9 and Tcf7l2 as targets of miR-338, while others are known from the literature. With this variety of target genes, miR-338 multiplies the effects of its activator Sox10. Besides miR-338, miR-335 and miR-155, miR-204 is under control of Sox10. It is a newly identified regulator with impact on proliferation and differentiation. Again this is possible by its variety of target genes. MiR-204 reduces proliferation of oligodendrocyte precursor cells by targeting Ccnd2 and forces differentiation via inhibition of Sox4. Probably, further yet unknown genes are among the targets of miR-204 in oligodendroglia. Finally, we extended our analysis to microRNAs downstream of Sox2 and Sox3. We had described that Sox2 and Sox3 are important for myelination. Now, that we technically achieved deletion of Sox2 and Sox3 in a cell culture system of purified primary mouse oligodendroglia, we could start screening analyses by microRNA- and mRNA-sequencing. These data are currently under research to understand the role of Sox2 and Sox3 in myelination and to compare it to the role of Sox10.
Projektbezogene Publikationen (Auswahl)
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2017. Transcription factor Sox10 regulates oligodendroglial Sox9 levels via microRNAs. Glia. 65, 1089-1102
Reiprich S, Cantone M, Weider M, Baroti T, Wittstatt J, Schmitt C, Küspert M, Vera J, Wegner M
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2019. A gene regulatory architecture that controls regionindependent dynamics of oligodendrocyte differentiation. Glia. 67, 825-843
Cantone M, Küspert M, Reiprich S, Lai X, Eberhardt M, Göttle P, Beyer F, Azim K, Küry P, Wegner M, Vera J
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2019. Crazy little thing called Sox - new insights in oligodendroglial Sox protein function. International Journal of Molecular Science. 20, 2713
Wittstatt J, Reiprich S, Küspert M
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2020. MicroRNA miR-204 regulates proliferation and differentiation of oligodendroglia in culture. Glia. 68, 2015-2027
Wittstatt J, Weider M, Wegner M, Reiprich S
