Abstract
Oligodendrocytes wrap and physically shield axons of the central nervous system with myelin sheaths, resulting in rapid signal transduction and accurate neuronal function. The complex oligodendroglial development from immature oligodendrocyte precursor cells (OPCs) to myelinating oligodendrocytes (OLs) is profoundly dependent on the activity of transcription factors of the Sox protein family. Target genes of the crucial regulator Sox10 have recently been expanded to microRNAs. Here, we report miR-204 as a novel transcriptional target of Sox10. Regulatory regions of miR-204 show responsiveness to and binding of Sox10 in reporter gene assays and electromobility shift assays. Once expressed, miR-204 inhibits OPC proliferation and facilitates differentiation into OLs in the presence of Sox10 as evident from overexpression in primary rat and mouse oligodendroglial cultures. Phenotypes are at least in part caused by miR-204-dependent repression of the pro-proliferative Ccnd2 and the differentiation inhibiting Sox4. These findings argue that the transcriptional activator Sox10 forces oligodendroglial cells to exit the cell cycle and start differentiation by gene inhibition via miR-204 induction.
Highlights
MicroRNAs are increasingly recognized as important regulatory factors in oligodendroglia in development and disease
In a quantitative RT-PCR-based high-throughput screening of miR expression in the oligodendroglial cell line Oln93, we identified a number of miRs that were strongly downregulated in the absence of Sox10 (Reiprich et al, 2017)
The lineage determining transcription factor Sox10 plays an essential role in oligodendroglia at all stages from the oligodendrocyte precursor cells (OPCs) to the mature OL
Summary
MicroRNAs (miRs) are increasingly recognized as important regulatory factors in oligodendroglia in development and disease. They are necessary when myelinating glia of the central nervous system (CNS) develop from oligodendrocyte precursor cells (OPCs) either during embryonic myelination or during remyelination in de- and dysmyelinating diseases such as multiple sclerosis and leukodystrophies (for review, see Galloway & Moore, 2016). Few miRs are characterized in their role of fine-tuning the complex network of transcription factors that controls differentiation from the OPC to the mature OL. MiR-338, miR-219, and miR-138 support differentiation of oligodendroglia by targeting mRNAs of factors that keep the cells in a precursor stage (Dugas et al, 2010; Zhao et al, 2010). MiR-204 fulfills an important function in the progression from OPCs to OLs downstream of Sox
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