Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany.
Int J Mol Sci. 2024 May 11;25(10):5234. doi: 10.3390/ijms25105234.
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 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.
Sox10 是一个含有 HMG 结构域的转录因子，在调节雪旺细胞存活和分化方面发挥着关键作用，并且在整个雪旺细胞谱系中表达。虽然 Sox10 在周围髓鞘形成中的重要性已得到充分证实，但人们对其在雪旺细胞发育早期阶段的作用知之甚少。在寻找 Sox10 在雪旺细胞前体中的直接靶基因时，发现了转录共抑制因子 Tle4。至少有两个基因上游的区域参与介导 Sox10 依赖性激活。一旦被诱导，Tle4 与 bHLH 转录抑制因子 Hes1 协同作用，通过阻止 Sox10 蛋白转录激活成熟基因，并通过抑制基因的已知增强子来抑制 Sox10 表达，从而对 Sox10 产生双重抑制作用。这种机制建立了一个调节障碍，防止 Sox10 在不成熟的雪旺细胞中过早激活参与分化和髓鞘形成的因子。将 Tle4 鉴定为 Sox10 的关键下游靶标，揭示了雪旺细胞发育早期阶段的基因调控网络。它揭示了一个精细的调节电路，微调了雪旺细胞分化和髓鞘基因表达的时间和程度。
