Abstract：
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.
摘要：
中枢神经系统的少突胶质细胞分化和髓鞘形成是由一个复杂的基因调控网络控制和协调的，该网络包含几个转录因子，包括Zfp488和Nkx2.2。尽管已证明在少突胶质细胞分化中的作用，但对Zfp488和Nkx2.2作用的确切模式知之甚少。包括他们的目标基因。这里,我们使用Zfp488和Nkx2.2的过表达来分化CG4细胞,以确定依赖于这些转录因子的少突胶质细胞表达谱的方面.虽然这两种转录因子主要被描述为抑制因子，检测到的变化主张作为激活剂的额外功能。在由Zfp488和Nkx2.2激活的基因中,G蛋白偶联受体Gpr37在髓鞘形成期间是重要的。与对Gpr37表达的积极作用一致，在小鼠的Zfp488-和Nkx2.2缺陷的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在体内都与Gpr37基因下游的一个调控区结合，没有一个调控区被单独的转录因子激活。仅在持续存在于少突胶质细胞中的转录因子Sox10存在下观察到Zfp488或Nkx2.2增加的激活。我们的结果表明，Zfp488和Nkx2.2在少突胶质细胞分化过程中也充当转录激活剂，并与Sox10合作以允许表达Gpr37作为髓鞘形成过程的调节剂。
