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: 10650855
• 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/10650855
• 关键词: Axon; Biological Models; Cell Lineage; Cells; Central Nervous System; Development; Disease; Dorsal; Epigenetic Process; Genetic Transcription; Goals; Image; Injury; Maps; Molecular; Motor; Mus; Myelin; Nervous System; Neural tube; Neuroglia; Neurons; Oligodendroglia; Pathway interactions; Prosencephalon; Signal Transduction; Specific qualifier value; Spinal Cord; Testing; Zebrafish; candidate identification; cell type; in vivo; insight; migration; myelination; nerve stem cell; notch protein; oligodendrocyte lineage; oligodendrocyte precursor; oligodendrocyte progenitor; precursor cell; progenitor; 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如何，髓鞘的神经胶质细胞类型 脊椎动物中枢神经系统是在发育过程中形成的。在腹侧脊髓和背侧 前脑，神经祖细胞首先产生神经元，其次是少突胶质前体细胞（OPC），该细胞（OPC） 迁移和分裂以填充神经管。随后，许多OPC停止划分和区分为 髓鞘少突胶质细胞。而我们对促进的机制有相当多的了解 少突胶质细胞分化和髓鞘形成，我们对调节的机制知之甚少 指定少突胶质细胞命运的祖细胞的最早步骤。基于我们的体内，基于现场成像的命运 映射研究，我们发现不同的脊髓和前脑祖细胞会产生神经元和 OPC。现在，我们已经使用了单细胞RNA-seq分析来识别这些前OPC的转录态 祖细胞，并确定了候选细胞中的程序和保守的细胞超支途径 在神经系统区域和跨脊椎动物之间。使用斑马鱼和小鼠作为模型系统， 该项目将确定指导神经祖细胞形成OPC的分子机制。具体的 AIM 1将检验一个假设，即先锋转录因子ASCL1建立表观遗传和 前OPC的转录状态。 AIM 2将研究Notch信号选择A的机制 前opc命运的神经祖细胞的子集。特定目标3将检验转录因子的假设 GSX2有助于指定前OPC状态和/或调节OPC过渡前的OPC。这个项目的结果 有可能对发育性髓鞘的重要新见解，髓鞘疾病的原因和 恢复疾病和损伤后髓磷脂的潜在策略。