ZFP191 control of the myelination program of oligodendrocytes

ZFP191 控制少突胶质细胞的髓鞘形成过程

• 批准号: 8089231
• 负责人: Brian J Popko
• 金额: $ 33.44万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089231
• 关键词: Address; Adult; Alleles; Animals; Asses; Astrocytes; Axon; Binding; Brain; Cell Maturation; Cell Nucleus; Cells; Cuprizone; DNA Binding; DNA-Binding Proteins; Development; Failure; Family; Gene Expression; Gene Targeting; Genes; Genetic Screening; Goals; Health; In Vitro; Maintenance; Messenger RNA; Molecular; Multiple Sclerosis; Mus; Mutant Strains Mice; Mutate; Mutation; Myelin; Myelin Sheath; Neurons; Nuclear; Nuclear Proteins; Oligodendroglia; Patients; Play; Process; Protein Binding; Proteins; Recovery; Role; Specificity; Staging; Stem cells; Tamoxifen; Tissues; Yeasts; Zinc Fingers; cell type; chromatin immunoprecipitation; design; enhancing factor; in vivo; insight; mature animal; member; mutant; myelination; nervous system disorder; programs; protein expression; protein protein interaction; recombinase; toxicant; transcription factor; yeast two hybrid system

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.

描述(申请人提供)：发育中的中枢神经系统轴突的髓鞘形成和成人脱髓鞘轴突的再髓鞘形成需要少突胶质前体细胞(OPC)迁移到它们的目标轴突，在那里它们成熟为髓鞘细胞。虽然已经确定了这些过程的一些关键因素，但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了解仍然不完整。我们已经确定了一种锌指蛋白(Zfp191)，当在小鼠中突变时，尽管存在正常数量的成熟的、突起延伸的少突胶质细胞，但导致中枢神经系统髓鞘的缺失。Zfp191小鼠突变体表达一系列髓鞘相关基因的水平显著降低，表明该蛋白参与了中枢神经系统髓鞘形成程序的控制。Zfp191属于核蛋白家族，其成员既包含DNA结合的锌指结构域，也包含负责蛋白质相互作用的扫描结构域。这项建议的目的是为了更好地了解Zfp191在髓鞘形成过程中所起的作用。Zfp191在所研究的所有组织和细胞类型中都有表达，包括星形胶质细胞和神经元，随着OPC分化为成熟的、有髓鞘的少突胶质细胞，Zfp191的mRNA水平不会改变。因此，我们将在这项提案中概述的研究中解决的一个关键问题是，Zfp191是否在少突胶质细胞中具有细胞自主功能，或者是否其他类型的细胞导致Zfp191突变体表现出的髓鞘异常。此外，我们将确定该蛋白的持续表达是否是维持髓鞘所必需的，我们还将评估该蛋白在重新髓鞘形成过程中是否具有类似的基本功能。我们还将通过测定ZFP191的DNA和蛋白质结合潜力来探索ZFP 191控制髓鞘形成程序的分子机制。相关性：本提案中描述的研究将侧重于少突胶质细胞成熟的最后阶段的分子控制，这将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疾病(如多发性硬化症)的轴突再髓鞘形成的策略是至关重要的。公共卫生相关性：脱髓鞘损伤后的重新髓鞘形成，如多发性硬化症患者所发生的那样，可以恢复神经元功能并提供轴突保护。这一建议的重点是我们在正向遗传学筛查中发现的一个基因(ZFP191)，该基因似乎对少突胶质细胞成熟的最后阶段至关重要。所描述的研究旨在加深我们对ZFP191调节髓鞘形成过程的最后阶段的机制的理解。