Temporal and Spatial Control of Oligodendrocyte Fate Specification

项目概要 该项目的长期目标是了解少突胶质细胞（髓鞘神经胶质细胞类型）如何 脊椎动物的中枢神经系统是在发育过程中形成的。在脊髓腹侧和背侧 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（OPC）， 迁移并分裂以填充神经管。随后，许多 OPC 停止分裂并分化为 髓鞘少突胶质细胞。尽管我们对促进机制了解相当多 少突胶质细胞分化和髓鞘形成，我们对调节少突胶质细胞分化和髓鞘形成的机制知之甚少。 确定少突胶质细胞命运祖细胞的最早步骤。基于我们体内基于实时成像的命运 绘图研究中，我们发现不同的脊髓和前脑祖细胞产生神经元和 原花青素。我们现在已经使用单细胞 RNA-seq 分析来鉴定这些 pre-OPC 的转录状态 祖细胞，并确定了保守的候选细胞内在程序和细胞外在途径 神经系统区域之间和脊椎动物物种之间。使用斑马鱼和小鼠作为模型系统， 该项目将确定引导神经祖细胞形成 OPC 的分子机制。具体 目标 1 将检验一个假设，即先锋转录因子 Ascl1 建立了表观遗传和 前OPCs的转录状态。目标 2 将研究 Notch 信号选择的机制 OPC 前命运的神经祖细胞子集。具体目标 3 将检验转录因子的假设 Gsx2 帮助指定预 OPC 状态和/或调节预 OPC 到 OPC 的转换。该项目的成果 有可能对发育性髓鞘形成、髓鞘疾病的原因和 疾病和损伤后恢复髓磷脂的潜在策略。

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.