Temporal and Spatial Control of Oligodendrocyte Fate Specification

少突胶质细胞命运规范的时间和空间控制

• 批准号: 10539047
• 负责人: Bruce H Appel
• 金额: $ 56.14万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539047
• 关键词: Axon; Biological Models; Cell Lineage; Cells; Development; Disease; Dorsal; Epigenetic Process; Genetic Transcription; Goals; Image; Injury; Molecular; Motor; Mus; Myelin; Nervous system structure; Neural tube; Neuraxis; Neuroglia; Neurons; Oligodendroglia; Pathway interactions; Prosencephalon; Signal Transduction; Specific qualifier value; Spinal Cord; Testing; Zebrafish; base; cell type; in vivo; insight; myelination; nerve stem cell; notch protein; oligodendrocyte lineage; oligodendrocyte precursor; oligodendrocyte progenitor; precursor cell; programs; single-cell RNA sequencing; stem cells; transcription factor

PROJECT SUMMARY The long-term goal of this project is to understand how oligodendrocytes, the myelinating glia cell type of the vertebrate central nervous system, are formed during development. In the ventral spinal cord and dorsal forebrain, neural progenitors first produce neurons followed by oligodendrocyte precursor cells (OPCs), which migrate and divide to populate the neural tube. Subsequently, many OPCs stop dividing and differentiate as myelinating oligodendrocytes. Whereas we know a considerable amount about the mechanisms that promote oligodendrocyte differentiation and myelination, we know very little about mechanisms that regulate the very earliest steps in specifying progenitors for oligodendrocyte fate. Based on our in vivo, live imaging-based fate mapping studies, we discovered that different spinal cord and forebrain progenitor cells produce neurons and OPCs. We have now used single cell RNA-seq analyses to identify a transcriptional state of these pre-OPC progenitors, and have identified candidate cell-intrinsic programs and cell-extrinsic pathways that are conserved between nervous system regions and across vertebrate species. Using zebrafish and mice as model systems, this project will identify the molecular mechanisms that guide formation of OPCs from neural progenitors. Specific Aim 1 will test a hypothesis that the pioneer transcription factor Ascl1 establishes the epigenetic and transcriptional state of pre-OPCs. Aim 2 will investigate the mechanisms by which Notch signaling selects a subset of neural progenitors for a pre-OPC fate. Specific Aim 3 will test a hypothesis that the transcription factor Gsx2 helps specify a pre-OPC state and/or regulates a pre-OPC to OPC transition. The results of this project have the potential for important new insights into developmental myelination, the causes of myelin disease and potential strategies to restore myelin following disease and injury.

项目摘要 该项目的长期目标是了解少突胶质细胞，即脊髓中的髓鞘神经胶质细胞类型， 脊椎动物的中枢神经系统是在发育过程中形成的。在腹侧脊髓和背侧 在前脑中，神经祖细胞首先产生神经元，然后是少突胶质细胞前体细胞（OPCs）， 迁移和分裂以形成神经管随后，许多OPC停止划分和分化， 髓鞘少突胶质细胞尽管我们知道相当多的促进机制， 少突胶质细胞分化和髓鞘形成，我们对调节这些细胞的机制知之甚少。 在指定少突胶质细胞命运的祖细胞的最早步骤。基于我们在体内的，基于实时成像的命运 通过定位研究，我们发现不同的脊髓和前脑祖细胞产生神经元， OPCs。我们现在已经使用单细胞RNA-seq分析来鉴定这些前OPC的转录状态， 祖细胞，并已确定候选细胞的内在程序和细胞的外在途径，是保守的 神经系统区域和脊椎动物物种之间的差异。使用斑马鱼和小鼠作为模型系统， 这个项目将确定从神经祖细胞引导OPCs形成的分子机制。具体 目的1将测试一个假设，即先驱转录因子Ascl 1建立了表观遗传和 前OPC的转录状态。目的2将研究Notch信号选择一个 前OPC命运的神经祖细胞的子集。具体目标3将测试一个假设，即转录因子 Gsx 2帮助指定OPC前状态和/或调节OPC前到OPC的转换。该项目的结果 有可能对髓鞘形成的发育、髓鞘疾病的原因和 在疾病和损伤后恢复髓鞘的潜在策略。