Transcriptional control of oligodendrocyte differentiation and myelination

少突胶质细胞分化和髓鞘形成的转录控制

• 批准号: 8535829
• 负责人: Mengsheng Qiu
• 金额: $ 30.53万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535829
• 关键词: Axon; Binding; Cell Differentiation process; Cell Line; Cell Maturation; Cells; Chickens; Cues; Data; Demyelinating Diseases; Development; Embryo; Ensure; Equilibrium; Gene Expression; Genes; Genetic; Knowledge; Maintenance; Molecular; Mutation; Myelin; Myelin Sheath; Natural regeneration; Neuraxis; Neuroglia; Neurologic; Nkx-2.2 protein; Oligodendroglia; Pathway interactions; Patients; Principal Investigator; Process; Production; Proteins; Regulation; Role; Series; Signal Transduction; Spinal Cord; Spinal cord injury patients; Testing; Transcriptional Regulation; Transgenic Animals; Undifferentiated; axon regeneration; inhibitor/antagonist; insight; mutant; myelination; oligodendrocyte precursor; precursor cell; premature; prevent; programs; promoter; remyelination; transcription factor; transmission process

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.

少突胶质细胞是在大脑中央所有区域中发现的有髓鞘神经胶质细胞 神经系统。少突胶质细胞的主要功能是形成髓鞘 轴突周围，以确保电信号的快速和忠实传输。 在发育过程中，少突胶质细胞前体细胞 (OPC) 必须经历 在完全成熟之前发生一系列形态和分子变化 分化为成熟的髓鞘少突胶质细胞。差异化和 少突胶质细胞的髓鞘形成过程受到转录的严格控制 因素。最近的研究表明Sox10转录因子直接 刺激 OPC 分化和髓磷脂基因表达。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，均在未分化 OPC 细胞中表达 在发育中的中枢神经系统中。而 Nkx2.2 和 Olig1 的功能是 促进 OPC 分化，Hes5 和 Id4 充当 OPC 成熟的抑制剂。这 这四个调节转录因子在控制 OL 中的功能关系 差异化尚未确定。在此应用中，我们假设 Nkx2.2通过抑制表达或功能间接增强OPC成熟 Hes5 和 Id4，但与 Olig1 协同作用促进 OPC 差异化。这些假设将在该提案的前两个目标中得到检验。 最近的数据表明，Nkx2.2 在分化的 OL 和 少突胶质细胞系中 Nkx2.2 的过度表达抑制 MBP 基因表达， 提高了 Nkx2.2 转变其角色成为髓磷脂阻遏物的可能性 成熟 OL 中的基因表达可防止髓鞘质过度生成。这 该提案的第三个目标将审查可能性。最后，我们将测试 假设成熟 OL 中 Sox10 的持续表达可维持 髓磷脂基因表达和髓鞘稳定性。 Sox10 和的相互作用 髓鞘 OL 细胞中的 Nkx2.2 可能负责髓磷脂的微妙平衡 生产和结构维护。 这一系列的研究可以帮助我们了解控制的分子途径 轴突髓鞘形成过程并提供分子发育的见解 刺激少突胶质细胞再生和髓鞘再生的方法 脱髓鞘疾病。

项目成果

MicroRNAs are essential for the developmental switch from neurogenesis to gliogenesis in the developing spinal cord.

• DOI: 10.1523/jneurosci.1169-10.2010
• 发表时间: 2010-06-16
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Zheng K;Li H;Zhu Y;Zhu Q;Qiu M
• 通讯作者: Qiu M

Olig3 is not involved in the ventral patterning of spinal cord.

Olig3 不参与脊髓的腹侧模式。

• DOI: 10.1371/journal.pone.0111076
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Liu Z;Hu X;Huang C;Zheng K;Takebayashi H;Cao C;Qiu M
• 通讯作者: Qiu M

Dynamic expression of secreted Frizzled-related protein 3 (sFRP3) in the developing mouse spinal cord and dorsal root ganglia.

分泌型卷曲相关蛋白 3 (sFRP3) 在发育中的小鼠脊髓和背根神经节中的动态表达

• DOI: 10.1016/j.neuroscience.2013.06.044
• 发表时间: 2013-09-17
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Zhao X;Huang H;Chen Y;Liu Y;Zhang Z;Ma Q;Qiu M
• 通讯作者: Qiu M

Necl-4/SynCAM-4 is expressed in myelinating oligodendrocytes but not required for axonal myelination.

Necl-4/SynCAM-4 在髓鞘少突胶质细胞中表达，但不是轴突髓鞘形成所必需的

• DOI: 10.1371/journal.pone.0064264
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhu Y;Li H;Li K;Zhao X;An T;Hu X;Park J;Huang H;Bin Y;Qiang B;Yuan J;Peng X;Qiu M
• 通讯作者: Qiu M

Co-localization of Nkx6.2 and Nkx2.2 homeodomain proteins in differentiated myelinating oligodendrocytes.

• DOI: 10.1002/glia.20937
• 发表时间: 2010-03
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Cai, Jun;Zhu, Qiang;Zheng, Kang;Li, Hong;Qi, Yingchuan;Cao, Qilin;Qiu, Mengsheng
• 通讯作者: Qiu, Mengsheng