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

项目摘要 少突胶质前体细胞（Oligodendrocyte precursor cells，OPCs）是中枢神经系统中增殖性最强、数量最多的细胞类型之一。 神经系统（CNS）。在发育过程中，OPCs广泛分布于灰质或白色物质区域， 并且容易分化产生少突胶质细胞，其负责绝缘神经元轴突， 髓磷脂在小鼠模型中的研究表明，OPCs和少突胶质细胞的异常发育是 神经系统疾病和紊乱如肌萎缩侧索硬化症（ALS）的潜在原因之一， 多发性硬化症（MS）和胶质母细胞瘤，最致命的脑癌。目前，尚不清楚OPCs如何 调节以填充灰质（GM）或白色物质（WM），以及负责的机制 选择性地维持许多OPCs处于未分化状态，而其他OPCs成熟为少突胶质细胞。之前 研究表明，转录因子ASCL 1在OPCs中差异表达， 在WM-OPCs中高于GM-OPCs。本提案中概述的实验旨在测试 假设ASCL 1水平指定OPCs的命运并决定其归巢， GM或WM中的属性。为了检验这一假设，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ASCL 1是否负责指定OPC命运， 大脑中的WM而不是GM。 具体目标2。使用ChIP-seq在OPCs中特异性鉴定ASCL 1的功能相关遗传靶标 和核糖标记 具体目标3。为了确定编码细胞表面蛋白的ASCL 1的新靶点Cntn 1是否起作用， 在ASCL 1下游介导OPCs归巢至WM。 ASCL 1和CNTN 1对于OPC发育、正常髓鞘形成和胶质瘤进展都是必需的， 转移我们预计，这项研究的完成将提供新的机制的见解，如何 OPC/少突胶质细胞相关的病理状况，如脱髓鞘、神经元变性和 癌症发生在中枢神经系统，同时也提供了一个切入点，潜在地操纵这些细胞 来治疗这些使人衰弱的疾病

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.