Temporal and Spatial Control of Oligodendrocyte Fate Specification

项目总结 这个项目的长期目标是了解少突胶质细胞是如何 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，神经前体细胞首先产生神经元，然后是少突胶质前体细胞(OPC)，这是 迁移和分裂以填充神经管。随后，许多OPC停止划分并分化为 髓鞘少突胶质细胞。鉴于我们知道相当多关于促进 少突胶质细胞分化和髓鞘形成，我们对调节 指定少突胶质细胞命运的祖细胞的最早步骤。基于我们在活体内，基于实时成像的命运 图谱研究，我们发现不同的脊髓和前脑前体细胞产生神经元和 OPC。我们现在已经使用单细胞rna-seq分析来确定这些opc前基因的转录状态。 并已确定了保守的候选细胞内在程序和细胞外在途径 在神经系统区域之间和脊椎动物物种之间。以斑马鱼和老鼠为模型系统， 该项目将确定引导神经前体细胞形成OPC的分子机制。特定的 目标1将检验一个假设，即先驱转录因子Ascl1建立表观遗传和 前OPC的转录状态。目标2将研究Notch信令选择 神经前体细胞的子集，代表了OPC前的命运。《特指目标3》将检验转录因子 GSX2帮助指定OPC前状态和/或调节OPC前到OPC的转换。这个项目的成果 有可能对发育中的髓鞘形成、髓鞘疾病的原因和 在疾病和损伤后恢复髓鞘的潜在策略。

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.