ZFP191 control of the myelination program of oligodendrocytes

6.项目概要/摘要 发育过程中中枢神经系统轴突的髓鞘形成和脱髓鞘轴突的髓鞘再生 成年人需要少突胶质细胞祖细胞（OPCs）迁移到它们的靶轴突， 成熟为髓鞘细胞。虽然已经确定了一些关键因素， 虽然我们对中枢神经系统髓鞘形成和髓鞘再生的分子控制的理解仍然存在， 不完整我们已经鉴定了一种锌指蛋白（Zfp 191），当在小鼠中突变时， 缺乏中枢神经系统髓鞘，尽管存在正常数量的成熟，过程延伸 少突胶质细胞ZFP 191小鼠突变体表达一系列髓鞘相关基因， 水平降低，表明该蛋白参与CNS髓鞘形成的控制。 程序. Zfp 191属于一个核蛋白家族，其成员包含DNA结合蛋白， 锌指结构域和SCAN结构域，它们负责蛋白质-蛋白质相互作用。的 该提案的目的是更好地了解Zfp 191在髓鞘形成中的作用 过程Zfp 191在所检查的所有组织和细胞类型中表达，包括星形胶质细胞和 Zfp 191 mRNA的水平不随OPCs分化为成熟的， 髓鞘少突胶质细胞因此，我们将在以下概述的研究中解决的一个关键问题是， 这一建议是Zfp 191是否在少突胶质细胞中具有细胞自主功能，或者是否在其他细胞中具有细胞自主功能。 细胞类型导致Zfp 191突变体显示的髓磷脂异常。而且还要 确定这种蛋白质的持续表达是否是维持髓磷脂所必需的 我们还将评估这种蛋白质是否在髓鞘再生中具有类似的基本功能 过程我们还将探讨ZFP 191控制髓鞘形成的分子机制。 通过确定其DNA和蛋白质结合潜力来编程。 相关性：本提案中描述的研究将侧重于最终的 少突胶质细胞成熟的阶段，其导致髓鞘形成程序的启动。一 更好地理解促进少突胶质细胞成熟的因素对我们的努力至关重要 开发促进脱髓鞘神经系统疾病（例如， 多发性硬化）。

6. Project Summary/Abstract The myelination of CNS axons during development and the remyelination of demyelinated axons in adults require oligodendrocyte progenitor cells (OPCs) to migrate to their target axons where they mature into myelinating cells. Although a number of critical factors have been identified for these processes, our understanding of the molecular control of CNS myelination and remyelination remains incomplete. We have identified a zinc finger protein (Zfp191) that when mutated in mice results in the absence of CNS myelin despite the presence of normal numbers of mature, process-extending oligodendrocytes. Zfp191 mouse mutants express an array of myelin-related genes at significantly reduced levels, suggesting that this protein participates in the control of the CNS myelination program. Zfp191 belongs to a family of nuclear proteins whose members contain both DNA binding zinc finger domains and SCAN domains, which are responsible for protein-protein interactions. The goal of this proposal is to gain a better understanding of the role that Zfp191 plays in the myelination process. Zfp191 is expressed in all tissues and cell-types examined, including astrocytes and neurons, and the level of Zfp191 mRNA does not change as OPCs differentiate into mature, myelinating oligodendrocytes. Thus, a critical question that we will address in the studies outlined in this proposal is whether Zfp191 has a cell autonomous function in oligodendrocytes or whether other cell types contribute to the myelin abnormalities displayed by the Zfp191 mutants. Moreover, we will determine if the continued expression of this protein is required for the maintenance of the myelin sheath, and we will also assess if this protein has a similar essential function in the remyelination process. We will also explore the molecular mechanism by which ZFP191 controls the myelination program by determining its DNA and protein binding potential. Relevance: The studies described in this proposal will focus on the molecular control of the final stages of oligodendrocyte maturation, which result in the initiation of the myelination program. A better understanding of the factors that enhance oligodendrocyte maturation is essential in our effort to develop strategies to promote axonal remyelination in demyelinating neurological disorders (e.g. multiple scelrosis).