ZFP191 control of the myelination program of oligodendrocytes

描述（由申请人提供）：发育期间CNS轴突的髓鞘形成和成人脱髓鞘轴突的髓鞘再生需要少突胶质细胞祖细胞（OPC）迁移至其靶轴突，在靶轴突中它们成熟为髓鞘形成细胞。虽然已经确定了一些关键因素，这些过程中，我们的理解中枢神经系统髓鞘形成和髓鞘再生的分子控制仍然不完整。我们已经确定了一个锌指蛋白（Zfp 191），当在小鼠中突变的结果在CNS髓鞘的情况下，尽管存在正常数量的成熟，过程延伸少突胶质细胞。Zfp 191小鼠突变体以显著降低的水平表达一系列髓鞘相关基因，表明该蛋白质参与CNS髓鞘形成程序的控制。Zfp 191属于核蛋白家族，其成员包含DNA结合锌指结构域和SCAN结构域，其负责蛋白质-蛋白质相互作用。该提案的目标是更好地了解Zfp 191在髓鞘形成过程中的作用。Zfp 191在所有检查的组织和细胞类型中表达，包括星形胶质细胞和神经元，并且Zfp 191 mRNA的水平在OPCs分化为成熟的髓鞘少突胶质细胞时不改变。因此，我们将在本提案中概述的研究中解决的一个关键问题是，Zfp 191是否在少突胶质细胞中具有细胞自主功能，或者其他细胞类型是否有助于Zfp 191突变体显示的髓鞘异常。此外，我们将确定这种蛋白质的持续表达是否是维持髓鞘所必需的，我们还将评估这种蛋白质在髓鞘再生过程中是否具有类似的基本功能。我们还将探索ZFP 191通过确定其DNA和蛋白质结合潜力来控制髓鞘形成程序的分子机制。相关性：在这个建议中描述的研究将集中在少突胶质细胞成熟的最后阶段的分子控制，这导致髓鞘形成程序的启动。更好地了解促进少突胶质细胞成熟的因素，对于我们努力开发促进脱髓鞘神经系统疾病（如多发性硬化症）轴突髓鞘再生的策略至关重要。公共卫生相关性：脱髓鞘损伤后的再髓鞘，如多发性硬化症患者中发生的那些，恢复神经元功能并提供轴突保护。这项建议的重点是一个基因（ZFP 191），我们已经确定了在一个正向遗传学筛选，似乎是必不可少的少突胶质细胞成熟的最后阶段。所描述的研究旨在进一步了解ZFP 191调节髓鞘形成过程最后阶段的机制。

DESCRIPTION (provided by applicant): 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 sclerosis). PUBLIC HEALTH RELEVANCE: Remyelination following demyelinating insults, such as those that occur in multiple sclerosis patients, restores neuronal function and provides axonal protection. This proposal is focused on a gene (ZFP191) that we have identified in a forward genetics screen that appears essential for the final stages of oligodendrocyte maturation. The studies described are designed to further our understanding of the mechanism by which ZFP191 regulates the final stages of the myelination process.