PDF(Pubmed)
Abstract：
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.
摘要：
含有HMG结构域的转录因子Sox10在调节雪旺氏细胞存活和分化中起关键作用，并在整个雪旺氏细胞系中表达。虽然其在外周髓鞘形成中的重要性已得到确认，对其在施万细胞发育早期的作用知之甚少。在寻找雪旺氏细胞前体中Sox10的直接靶基因时，鉴定了转录共阻遏子Tle4。Tle4基因上游的至少两个区域似乎参与介导Sox10依赖性激活。一旦被诱导，Tle4与bHLH转录抑制因子Hes1协同工作，并通过阻止Sox10蛋白转录激活成熟基因并通过已知的基因增强子抑制Sox10表达，对Sox10发挥双重抑制作用。该机制建立了调节屏障，可防止未成熟雪旺细胞中Sox10参与分化和髓磷脂形成的因子过早激活。Tle4作为Sox10的关键下游靶标的鉴定揭示了施万细胞发育早期阶段的基因调控网络。它揭示了一个复杂的调节电路，该电路可以微调雪旺氏细胞分化和髓磷脂基因表达的时间和程度。
