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中发现的髓鞘形成神经胶质细胞。少突胶质细胞的主要功能是在轴突周围形成髓鞘，以确保电信号的快速和可靠传输。在发育过程中，少突胶质细胞前体细胞（OPCs）在完全分化为成熟的有髓鞘少突胶质细胞之前必须经历一系列形态和分子变化。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分化受到其他转录因子（TF）的严格调控，包括Nkx2.2，Olig1，Hes5和Id4，所有这些都在发育中的中枢神经系统中的未分化OPC细胞中表达。虽然Nkx2.2和Olig1起促进OPC分化的作用，但Hes5和Id4起OPC成熟的抑制剂的作用。这四种调节性TF在控制OL分化中的功能关系尚未确定。在本申请中，我们假设Nkx2.2通过抑制Hes5和Id4的表达或功能间接增强OPC成熟，但与Olig1协同作用促进OPC分化。这些假设将在提案的前两个目标中得到检验。最近的数据显示，Nkx2.2在分化的OL中快速下调，并且在少突胶质细胞系中Nkx2.2的过表达抑制MBP基因表达，提高了Nkx2.2将其作用转变为成熟OL中髓鞘基因表达的阻遏物以防止过度髓鞘产生的可能性。将在提案的第三个目标中审查这种可能性。最后，我们将测试的假设，Sox10的持续表达在成熟的OLs功能，以维持髓鞘基因的表达和髓鞘的稳定性。Sox10和Nkx2.2在髓鞘形成OL细胞中的相互作用可能负责髓鞘产生和结构维持的微妙平衡。这一系列研究可以帮助我们了解控制轴突髓鞘形成过程的分子途径，并为开发刺激脱髓鞘疾病中少突胶质细胞再生和髓鞘再生的分子方法提供见解。公共卫生相关性：这些研究将为控制中枢神经系统发育中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。从这项研究中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，并为促进神经系统患者和脊髓损伤患者的少突胶质细胞再生和轴突髓鞘再生提供线索。

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.