Transcriptional control of OPC fate specification and homing to gray matter and white matter in the CNS

项目总结 少突胶质前体细胞是中枢神经系统中增殖能力最强、含量最丰富的细胞类型之一。 神经系统(CNS)。在发育过程中，OPC广泛分布在灰质或白质区域， 并且很容易分化成少突胶质细胞，这些少突胶质细胞负责将神经元轴突与 髓鞘。对小鼠模型的研究表明，OPC和少突胶质细胞的异常发育是 肌萎缩侧索硬化症(ALS)等神经系统疾病的根本原因之一， 多发性硬化症(MS)和胶质母细胞瘤，这是最致命的脑癌。目前，还不清楚OPC是如何 调节以填充灰质(GM)或白质(WM)，以及什么机制负责 选择性地维持许多OPC处于未分化状态，而其他OPC则成熟为少突胶质细胞。之前 研究表明，转录因子ASCL1在OPC中有差异表达，在OPC中它相对 WM-OPC高于GM-OPC。本提案中概述的实验旨在测试总体 假设ASCL1的水平决定了OPC的命运，并决定了它们的归宿和 GM或WM中的属性。为了验证这一假设，拟议的研究将追求以下具体目标。 具体目标1.确定持续高水平的ASCL1是否负责规定OPC命运和 在大脑中回归到WM而不是GM。 特定目的2.利用CHIP-SEQ鉴定OPC中ASCL1的功能相关遗传靶点 还有Ribo-Tag。 具体目的3.确定编码细胞表面蛋白的ASCL1的新靶点Cntn1是否具有功能 ASCL1的下游，以调解OPC归巢到WM。 ASCL1和CNTN1对于OPC的发展、正常的髓鞘形成和胶质瘤的进展以及 转移。我们预计，这项研究的完成将提供新的机械洞察力，了解如何 与OPC/少突胶质细胞相关的病理情况，如脱髓鞘、神经元变性和 癌症发生在中枢神经系统，同时也为潜在地操纵这些细胞提供了一个切入点 治疗这些令人衰弱的疾病。

PROJECT SUMMARY Oligodendrocyte precursor cells (OPCs) are one the most proliferative and abundant cell types in the central nervous system (CNS). During development, OPCs widely dispersed into areas of gray matter or white matter, and readily differentiate to give rise to oligodendrocytes, which are responsible for insulating neuronal axons with myelin. Studies in mouse models have revealed that abnormal development of OPCs and oligodendrocytes is one of the underlying causes of neurological diseases and disorders such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and glioblastoma, the deadliest of brain cancers. Currently, it is unknown how OPCs are regulated to populate the gray matter (GM) or white matter (WM), and what mechanisms are responsible for selectively maintaining many OPCs in undifferentiated state while others mature into oligodendrocytes. Prior studies demonstrate that the transcription factor, ASCL1, is differentially expressed in OPCs, where it is relatively higher in WM-OPCs than in GM-OPCs. Experiments outlined in this proposal are designed to test the overall hypothesis that the level of ASCL1 specifies the fate of OPCs and determines their homing and properties in the GM or WM. To test this hypothesis, the proposed study will pursue the following specific aims. Specific Aim 1. To determine if a sustained high level of ASCL1 is responsible for specifying OPC fate and homing to WM over GM in the brain. Specific Aim 2. To identify functionally relevant genetic targets of ASCL1 specifically in OPCs using ChIP-seq and Ribo-Tag. Specific Aim 3. To determine if Cntn1, a novel target of ASCL1 that encodes for a cell surface protein, functions downstream of ASCL1 to mediate the homing of OPCs to the WM. Both ASCL1 and CNTN1 are essential for OPC development, proper myelination, and glioma progression and metastasis. We anticipate that completion of this study will offer new mechanistic insights into how OPC/oligodendrocyte related pathological conditions such as demyelination, neuronal degeneration, and cancers arise in the CNS, while at the same time also provide an entry point to potentially manipulate these cells for the treatment of these debilitating diseases.