ZFP191 control of the myelination program of oligodendrocytes

6.项目摘要/摘要 中枢神经系统轴突发育过程中的髓鞘形成和脱髓鞘轴突的再髓鞘形成 成人需要少突胶质前体细胞(OPC)迁移到他们的靶轴突，在那里他们 成熟为髓鞘细胞。尽管已经确定了导致这些问题的一些关键因素 过程，我们对中枢神经系统髓鞘形成和再髓鞘形成的分子控制的理解 不完整。我们已经确定了一种锌指蛋白(Zfp191)，当在小鼠身上发生突变时，会导致 尽管存在正常数量的成熟、突起延伸的中枢神经系统髓鞘，但缺乏中枢神经系统髓鞘 少突胶质细胞。Zfp191小鼠突变体显著表达一系列髓鞘相关基因 水平降低，表明该蛋白参与了中枢神经系统髓鞘形成的控制 程序。Zfp191属于核蛋白家族，其成员包含DNA结合 锌指结构域和扫描结构域，它们负责蛋白质之间的相互作用。这个 这项建议的目的是更好地了解Zfp191在髓鞘形成中所起的作用 进程。Zfp191在所检测的所有组织和细胞类型中都有表达，包括星形胶质细胞和 Zfp191基因的表达水平不随OPC向成熟细胞分化而改变。 髓鞘少突胶质细胞。因此，我们将在 这一建议是Zfp191在少突胶质细胞中是否具有细胞自主功能，还是其他 Zfp191突变体表现出的髓鞘异常与细胞类型有关。此外，我们还将 确定该蛋白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在髓鞘再分化过程中是否具有类似的基本功能 进程。我们还将探索ZFP191控制髓鞘形成的分子机制 程序通过确定其DNA和蛋白质结合潜力。 相关性：本提案中描述的研究将重点放在最终的分子控制上 少突胶质细胞成熟的阶段，这导致髓鞘形成程序的启动。一个 更好地了解促进少突胶质细胞成熟的因素对我们的努力是至关重要的。 发展促进脱髓鞘神经疾病轴突再髓鞘形成的策略(例如： 多发性瘢痕病)。

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).