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: 8507811
• 负责人: Brian J Popko
• 金额: $ 32.27万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507811
• 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 Proteins; Oligodendroglia; Patients; Play; Process; Protein Binding; Proteins; Recovery; Role; Specificity; Staging; Stem cells; Tamoxifen; Tissues; Yeasts; Zinc Fingers; abstracting; 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; remyelination; toxicant; transcription factor; yeast two hybrid system

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).

6. 项目总结/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 (OPC) 迁移到其目标轴突，在那里它们 成熟为髓鞘细胞。尽管已经确定了导致这些问题的许多关键因素 过程中，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。我们已经鉴定出一种锌指蛋白（Zfp191），当它在小鼠体内发生突变时，会导致 尽管存在正常数量的成熟、过程延伸的中枢神经系统髓磷脂，但仍缺乏中枢神经系统髓磷脂 少突胶质细胞。 Zfp191小鼠突变体显着表达一系列髓磷脂相关基因 水平降低，表明该蛋白质参与中枢神经系统髓鞘形成的控制 程序。 Zfp191 属于核蛋白家族，其成员同时包含 DNA 结合 锌指结构域和 SCAN 结构域，负责蛋白质-蛋白质相互作用。这 该提案的目标是更好地了解 Zfp191 在髓鞘形成中所起的作用 过程。 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 神经元中，Zfp191 mRNA 的水平不会随着 OPC 分化为成熟、 髓鞘少突胶质细胞。因此，我们将在研究中解决的一个关键问题 这个提议是Zfp191是否在少突胶质细胞中具有细胞自主功能或者是否有其他功能 细胞类型导致 Zfp191 突变体表现出髓磷脂异常。此外，我们将 确定维持髓磷脂是否需要该蛋白的持续表达 鞘，我们还将评估该蛋白质在髓鞘再生中是否具有类似的基本功能 过程。我们还将探讨ZFP191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进行编程。 相关性：本提案中描述的研究将重点关注最终结果的分子控制 少突胶质细胞成熟的阶段，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于我们的努力至关重要 制定促进脱髓鞘神经系统疾病（例如神经系统疾病）中轴突髓鞘再生的策略 多发性硬化症）。