Transcriptional control of oligodendrocyte differentiation and myelination

描述（由申请人提供）：少突胶质细胞是在中枢神经系统的所有区域发现的髓鞘胶质细胞。少突胶质细胞的主要功能是在轴突周围形成髓鞘，以保证电信号的快速、准确传递。在发育过程中，少突胶质细胞前体细胞（oligodendrocytes precursor cells, OPCs）在完全分化为成熟的髓鞘性少突胶质细胞之前，需要经历一系列形态和分子上的变化。少突胶质细胞的分化和髓鞘形成过程受到转录因子的严格控制。最近的研究表明，Sox10转录因子直接刺激OPC分化和髓鞘基因表达。然而，OPC的分化受到其他转录因子（TFs）的严格调控，包括Nkx2.2、Olig1、Hes5和Id4，这些转录因子均在发育中的中枢神经系统未分化的OPC细胞中表达。Nkx2.2和Olig1促进OPC分化，Hes5和Id4抑制OPC成熟。这四种调节性tf在控制OL分化中的功能关系尚未确定。在这项应用中，我们假设Nkx2.2通过抑制Hes5和Id4的表达或功能间接促进OPC成熟，但与Olig1协同促进OPC分化。这些假设将在提案的前两个目标中得到检验。最近的研究表明，Nkx2.2在分化的OLs中被迅速下调，而在少突胶质细胞中Nkx2.2的过表达会抑制MBP基因的表达，这表明Nkx2.2可能在成熟的OLs中转变其作用，成为髓磷脂基因表达的抑制因子，以防止髓磷脂的过量产生。这一可能性将在提案的第三个目标中加以审查。最后，我们将验证成熟OLs中Sox10的持续表达是否具有维持髓鞘基因表达和髓鞘稳定性的功能。髓鞘OL细胞中Sox10和Nkx2.2的相互作用可能负责髓鞘生成和结构维持的微妙平衡。这一研究有助于我们了解控制轴突髓鞘形成过程的分子途径，并为脱髓鞘疾病中刺激少突胶质细胞再生和再髓鞘形成的分子方法的发展提供见解。公共卫生相关性：拟议的研究将为发育中的中枢神经系统中控制少突胶质细胞分化和髓鞘基因表达的转录因子的功能和调控提供重要信息。本研究获得的知识可以帮助我们了解控制少突胶质细胞分化和髓鞘形成的分子途径，为促进神经系统患者和脊髓损伤患者少突胶质细胞再生和轴突再髓鞘形成提供线索。

DESCRIPTION (provided by applicant): Oligodendrocytes are myelinating glial cells found in all regions of the central nervous system. The major function of oligodendrocytes is to form myelin sheaths around axons to ensure the rapid and faithful transmission of electrical signals. During development, oligodendrocytes precursor cells (OPCs) have to go through a series of morphological and molecular changes before they become fully differentiated into mature myelinating oligodendrocytes. The differentiation and myelination processes of oligodendrocytes are tightly controlled by transcription factors. Recent studies have demonstrated that Sox10 transcription factor directly stimulates OPC differentiation and myelin gene expression. However, OPC differentiation is tightly regulated by other transcription factors (TFs) including Nkx2.2, Olig1, Hes5 and Id4, all of which are expressed in undifferentiated OPC cells in the developing central nervous system. While Nkx2.2 and Olig1 function to promote OPC differentiation, Hes5 and Id4 act as inhibitors of OPC maturation. The functional relationship of these four regulatory TFs in the control of OL differentiation has not been determined. In this application, we hypothesize that Nkx2.2 enhances OPC maturation indirectly by suppressing the expression or function of Hes5 and Id4, but functions synergistically with Olig1 in promoting OPC differentiation. These hypotheses will be tested in the first two aims of the proposal. Recent data showed that Nkx2.2 is rapidly down-regulated in differentiated OLs and over-expression of Nkx2.2 in oligodendrocyte cell line inhibits MBP gene expression, raising the possibility that Nkx2.2 switches its role to become a repressor of myelin gene expression in mature OLs to prevent excessive myelin production. This possibility will be examined in the third aim of the proposal. Finally, we will test the hypothesis that persistent expression of Sox10 in mature OLs functions to maintain myelin gene expression and myelin sheath stability. The interplay of Sox10 and Nkx2.2 in myelinating OL cells may be responsible for the delicate balance of myelin production and structural maintenance. This line of study could help us understand molecular pathways that control axonal myelination process and provide insights into the development of molecular approaches to stimulate oligodendrocyte regeneration and remyelination in demyelinating diseases. PUBLIC HEALTH RELEVANCE: The proposed studies will provide important information on the function and regulations of transcription factors that control oligodendrocyte differentiation and myelin gene expression in the developing central nervous system. Knowledge obtained from this study can help us understand the molecular pathways that govern the differentiation and myelination of oligodendrocytes, and provide cues for promoting oligodendrocyte regeneration and axonal remyelination in neurological patients and spinal cord injury patients.