Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Glia. 2024 Jul;72(7):1304-1318. doi: 10.1002/glia.24530. Epub 2024 Mar 28.
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.
少突胶质细胞在中枢神经系统中的分化和髓鞘形成受到一个复杂的基因调控网络的控制和协调，该网络包含几个转录因子，包括 Zfp488 和 Nkx2.2。尽管它们在少突胶质细胞分化中的作用已得到证实，但关于 Zfp488 和 Nkx2.2 的确切作用模式，包括其靶基因，知之甚少。在这里，我们在分化的 CG4 细胞中过表达 Zfp488 和 Nkx2.2，以确定依赖于这些转录因子的少突胶质细胞表达谱的各个方面。尽管这两种转录因子主要被描述为抑制剂，但检测到的变化表明它们具有额外的激活作用。在 Zfp488 和 Nkx2.2 激活的基因中，G 蛋白偶联受体 Gpr37 是髓鞘形成过程中的一个重要基因。与对 Gpr37 表达的正向影响一致，在小鼠中 Zfp488 和 Nkx2.2 缺陷型少突胶质细胞中观察到 G 蛋白偶联受体的下调。我们还鉴定了 Gpr37 基因的几个潜在调控区。尽管 Zfp488 和 Nkx2.2 都在体内结合到 Gpr37 基因下游的一个调控区，但没有一个调控区被任一转录因子单独激活。只有在 Sox10 存在的情况下，Zfp488 或 Nkx2.2 的激活才会增加，Sox10 是一种在少突胶质细胞中持续存在的转录因子。我们的结果表明，Zfp488 和 Nkx2.2 在少突胶质细胞分化过程中也作为转录激活剂发挥作用，并与 Sox10 合作，允许 Gpr37 的表达作为髓鞘形成过程的调节剂。
