Sox10 and MRF: Interplay of two transcription factors as cornerstone of the regulatory network in myelinating oligodendrocytes

脊椎动物神经系统的正常功能需要沿着由中枢中的少突胶质细胞和外周神经系统中的许旺细胞形成髓鞘的轴突的快速跳跃传导沿着。Sox10是迄今为止鉴定的唯一一种对两种神经胶质细胞类型的髓鞘形成至关重要的转录因子。尽管Sox10在雪旺细胞髓鞘形成过程中的功能已经被表征到分子水平，但关于其在髓鞘形成少突胶质细胞中的作用知之甚少。因此，该提议旨在阐明Sox10在驱动少突胶质细胞髓鞘形成的调控网络中的分子功能。基于我们的初步结果，我们将调查的假设，Sox10，可能与支持因子和染色质重塑机械的帮助下，诱导表达MRF作为另一种转录因子，一旦诱导，与其诱导剂Sox10合作，激活髓鞘基因的表达，并开始髓鞘形成程序在少突胶质细胞。通过在全球范围内确定Sox10、MRF以及两者结合的靶基因，我们将获得对髓鞘形成程序及其潜在调控回路的前所未有的见解。我们的研究将增加我们对少突胶质细胞髓鞘形成及其调控的认识。它们将有助于更好地了解髓鞘疾病的机制，并可能有助于制定疾病治疗策略。

Normal function of the vertebrate nervous system requires rapid saltatory conduction along axons myelinated by oligodendrocytes in the central and Schwann cells in the peripheral nervous system. Sox10 is the only transcription factor identified so far that is essential for myelination in both glial cell types. Whereas Sox10 function during Schwann cell myelination has been characterized to the molecular level, much less is known about its actions in myelinating oligodendrocytes. Therefore this proposal aims to unravel the molecular function of Sox10 within the regulatory network that drives myelination in oligodendrocytes. Based on our preliminary results, we will investigate the hypothesis that Sox10, possibly with the help of supporting factors and the chromatin remodelling machinery, induces expression of MRF as another transcription factor that once induced, cooperates with its inducer Sox10 to activate myelin gene expression and start the myelination program in oligodendrocytes. By identifying target genes for Sox10, MRF and the combination of both on a global scale, we will obtain unprecedented insights into the myelination program and its underlying regulatory circuits. Our studies will increase our knowledge about myelination and its regulation in oligodendrocytes. They will help to better understand myelin disease mechanisms and could be instrumental in developing strategies for disease treatment.