Oligodendrocyte differentiation and myelination in the central nervous system are controlled and coordinated by a complex gene regulatory network that contains several transcription factors, including Zfp488 and Nkx2.2. Despite the proven role in oligodendrocyte differentiation little is known about the exact mode of Zfp488 and Nkx2.2 action, including their target genes. Here, we used overexpression of Zfp488 and Nkx2.2 in differentiating CG4 cells to identify aspects of the oligodendroglial expression profile that depend on these transcription factors. Although both transcription factors are primarily described as repressors, the detected changes argue for an additional function as activators. Among the genes activated by both Zfp488 and Nkx2.2 was the G protein‐coupled receptor Gpr37 that is important during myelination. In agreement with a positive effect on Gpr37 expression, downregulation of the G protein‐coupled receptor was observed in Zfp488‐ and in Nkx2.2‐deficient oligodendrocytes in the mouse. We also identified several potential regulatory regions of the Gpr37 gene. Although Zfp488 and Nkx2.2 both bind to one of the regulatory regions downstream of the Gpr37 gene in vivo, none of the regulatory regions was activated by either transcription factor alone. Increased activation by Zfp488 or Nkx2.2 was only observed in the presence of Sox10, a transcription factor continuously present in oligodendroglial cells. Our results argue that both Zfp488 and Nkx2.2 also act as transcriptional activators during oligodendrocyte differentiation and cooperate with Sox10 to allow the expression of Gpr37 as a modulator of the myelination process.

The HMG-domain containing transcription factor Sox10 plays a crucial role in regulating Schwann cell survival and differentiation and is expressed throughout the entire Schwann cell lineage. While its importance in peripheral myelination is well established, little is known about its role in the early stages of Schwann cell development. In a search for direct target genes of Sox10 in Schwann cell precursors, the transcriptional co-repressor Tle4 was identified. At least two regions upstream of the Tle4 gene appear involved in mediating the Sox10-dependent activation. Once induced, Tle4 works in tandem with the bHLH transcriptional repressor Hes1 and exerts a dual inhibitory effect on Sox10 by preventing the Sox10 protein from transcriptionally activating maturation genes and by suppressing Sox10 expression through known enhancers of the gene. This mechanism establishes a regulatory barrier that prevents premature activation of factors involved in differentiation and myelin formation by Sox10 in immature Schwann cells. The identification of Tle4 as a critical downstream target of Sox10 sheds light on the gene regulatory network in the early phases of Schwann cell development. It unravels an elaborate regulatory circuitry that fine-tunes the timing and extent of Schwann cell differentiation and myelin gene expression.

The plant homeodomain finger protein Phf8 is a histone demethylase implicated by mutation in mice and humans in neural crest defects and neurodevelopmental disturbances. Considering its widespread expression in cell types of the central nervous system, we set out to determine the role of Phf8 in oligodendroglial cells to clarify whether oligodendroglial defects are a possible contributing factor to Phf8‐dependent neurodevelopmental disorders. Using loss‐ and gain‐of‐function approaches in oligodendroglial cell lines and primary cell cultures, we show that Phf8 promotes the proliferation of rodent oligodendrocyte progenitor cells and impairs their differentiation to oligodendrocytes. Intriguingly, Phf8 has a strong positive impact on Olig2 expression by acting on several regulatory regions of the gene and changing their histone modification profile. Taking the influence of Olig2 levels on oligodendroglial proliferation and differentiation into account, Olig2 likely acts as an important downstream effector of Phf8 in these cells. In line with such an effector function, ectopic Olig2 expression in Phf8‐deficient cells rescues the proliferation defect. Additionally, generation of human oligodendrocytes from induced pluripotent stem cells did not require PHF8 in a system that relies on forced expression of Olig2 during oligodendroglial induction. We conclude that Phf8 may impact nervous system development at least in part through its action in oligodendroglial cells.

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The transcription factor Sox10 is an important determinant of oligodendroglial identity and influences oligodendroglial development and characteristics at various stages. Starting from RNA-seq data, we here show that the expression of several voltage-gated ion channels with known expression and important function in oligodendroglial cells depends upon Sox10. These include the Na_v1.1, Ca_v2.2, K_v1.1, and Kir4.1 channels. For each of the four encoding genes, we found at least one regulatory region that is activated by Sox10 in vitro and at the same time bound by Sox10 in vivo. Cell-specific deletion of Sox10 in oligodendroglial cells furthermore led to a strong downregulation of all four ion channels in a mouse model and thus in vivo. Our study provides a clear functional link between voltage-gated ion channels and the transcriptional regulatory network in oligodendroglial cells. Furthermore, our study argues that Sox10 exerts at least some of its functions in oligodendrocyte progenitor cells, in myelinating oligodendrocytes, or throughout lineage development via these ion channels. By doing so, we present one way in which oligodendroglial development and properties can be linked to neuronal activity to ensure crosstalk between cell types during the development and function of the central nervous system.

Oligodendroglial cells generate myelin sheaths in the vertebrate central nervous system to render rapid saltatory conduction possible and express the highly related Sox8, Sox9 and Sox10 transcription factors. While Sox9 and Sox10 fulfill crucial regulatory roles, Sox8 has only a limited impact on oligodendroglial development and myelination. By replacing Sox10 with Sox8 or Sox9 in the oligodendroglial Oln93 cell line, and comparing the expression profiles, we show here that Sox8 regulates the same processes as Sox10 and Sox9, but exhibits a substantially lower transcriptional activity under standard culture conditions. Sox8 influences fewer genes in their expression and changes their expression level less drastically, despite comparable binding to relevant regulatory regions in oligodendroglial cells. Therefore, it is likely that Sox8 and Sox10 vary in their transcriptional activity because of differences in their interactions with partner proteins. Intriguingly, it is the aminoterminal one third of the Sox protein that is responsible for the differential activities of Sox8 and Sox10, rather than the carboxyterminal two thirds that contain the known transactivation domains. Our study aims to provide an understanding of the relationship of Sox8 and Sox10 as paralogous transcription factors and their degree of functional redundancy in oligodendroglial cells, along with implications for health and disease.