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: 7781735
• 负责人: Brian J Popko
• 金额: $ 34.13万
• 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/7781735
• 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; In Vitro; Maintenance; Messenger RNA; Molecular; Multiple Sclerosis; Mus; Mutant Strains Mice; Mutate; Mutation; Myelin; Myelin Sheath; Neurons; Nuclear; Nuclear Protein; Nuclear Proteins; Oligodendroglia; Patients; Play; Process; Protein Binding; Proteins; Recovery; Role; Scanning; 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; public health relevance; 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（由申请人提供）：发育过程中中枢神经系统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祖细胞（OPC）迁移到其目标轴突，并在其中成熟为髓鞘细胞。尽管已经确定了这些过程的许多关键因素，但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不完整。我们已经鉴定出一种锌指蛋白（Zfp191），当该蛋白在小鼠体内发生突变时，会导致中枢神经系统髓磷脂的缺失，尽管存在正常数量的成熟、过程延伸的少突胶质细胞。 Zfp191 小鼠突变体表达一系列髓磷脂相关基因的水平显着降低，表明该蛋白参与中枢神经系统髓鞘形成程序的控制。 Zfp191 属于核蛋白家族，其成员包含 DNA 结合锌指结构域和负责蛋白质间相互作用的 SCAN 结构域。该提案的目的是更好地了解 Zfp191 在髓鞘形成过程中发挥的作用。 Zfp191 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 Zfp191 mRNA 的水平不会随着 OPC 分化为成熟的髓鞘少突胶质细胞而改变。因此，我们将在本提案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，或者其他细胞类型是否导致 Zfp191 突变体表现出的髓磷脂异常。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，并且我们还将评估该蛋白在髓鞘再生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 ZFP191 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重点关注少突胶质细胞成熟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制定促进脱髓鞘神经系统疾病（例如多发性硬化症）中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（例如多发性硬化症患者发生的脱髓鞘损伤）后的髓鞘再生可恢复神经元功能并提供轴突保护。该提案的重点是我们在正向遗传学筛选中发现的一个基因（ZFP191），该基因对于少突胶质细胞成熟的最后阶段至关重要。所述研究旨在进一步了解 ZFP191 调节髓鞘形成过程最后阶段的机制。