Role of DYT6 Dystonia Protein THAP1 in Oligodendroglial Mediated ECM Homeostasis During CNS Development

DYT6 肌张力障碍蛋白 THAP1 在中枢神经系统发育过程中少突胶质细胞介导的 ECM 稳态中的作用

• 批准号: 10669851
• 负责人: WILLIAM T. DAUER
• 金额: $ 44.15万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669851
• 关键词: 3-Dimensional; Adult; Astrocytes; Automobile Driving; Brain; Cell Lineage; Cell Maturation; Cells; ChIP-seq; Childhood; Chondroitin Sulfates; Complex; Cre driver; Cytoskeleton; Data; Defect; Development; Dystonia; Dystonic Disorder; Enzymes; Extracellular Matrix; GAG Gene; Generations; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Impairment; In Situ; In Vitro; Light; Mediating; Metabolic Pathway; Metabolism; Molecular; Motor; Motor Skills; Movement Disorders; Mutate; Neurodevelopmental Disorder; Neuroglia; Neuronal Plasticity; Neurons; Oligodendroglia; Pathogenesis; Pathway interactions; Play; Polysaccharides; Process; Proteins; Publishing; Regulation; Research; Role; Signal Transduction; Synaptic plasticity; Testing; Transcriptional Regulation; Work; YY1 Transcription Factor; autocrine; base; cell type; chondroitin sulfate glycosaminoglycan; defined contribution; in vivo; loss of function; loss of function mutation; mature animal; motor disorder; motor learning; myelination; nervous system development; neural circuit; neurodevelopment; novel; oligodendrocyte lineage; oligodendrocyte progenitor; paracrine; programs; scaffold; stem cells; transcription factor; transcriptomics

Abstract / Project Summary The brain extracellular matrix (ECM) is a complex three-dimensional milieu that has a profound influence on synaptic plasticity and myelination during development. The pathways and cell types driving ECM generation during brain development are poorly understood. This proposal investigates a recently identified cellular pathway that controls ECM composition from the oligodendrocyte progenitor cells (OPCs). This discovery was made through studies of the transcription factor THAP1, which is mutated in the neurodevelopmental movement disorder DYT-THAP1 (DYT6) dystonia. Previous work identified a critical role for THAP1 in developmental myelination. Loss of THAP1 in the oligodendrocyte (OL) lineage impairs the progression of OPC into mature myelinating OLs. Recent work has established that THAP1 mediates OL differentiation in large part by controlling the composition of secreted chondroitin sulfate (CS) GAGs, a class of long unbranched polysaccharides and core-constituents of the ECM, which are inhibitory to OL differentiation. The hypothesis that OPCs regulate ECM composition is new, and the transcription factor THAP1, together with its partner YY1, provides an inroad to delineating the cellular mechanisms that regulate ECM composition during CNS development. The proposed studies will establish a molecular understanding of the regulation of ECM and myelination by THAP1. Aim 1 will use ChIP-seq and transcriptomic studies to test the hypothesis that THAP1 and its co-regulatory transcription factor YY1 regulate GAG metabolism through a shared pathway in differentiating OPCs. Both transcription factors have established roles in myelination and cause human dystonia when mutated. Aim 2 will test the hypothesis that OPCs are important contributors to developmentally regulated CS-GAG composition of the brain ECM and define the relative contribution of other CNS cell types, and the role of THAP1 in this process. Aim 3 test the hypothesis that THAP1- dependent OL maturation is required for normal motor learning and define THAP1-dependent changes in ECM pathway genes induced by motor learning. These studies will advance our understanding of the mechanisms by which glia and ECM contribute to CNS motor function and will shed light on how disruption of these processes contribute to pathogenesis of dystonia and other neurodevelopmental disorders.

摘要 /项目摘要 大脑细胞外基质（ECM）是一个复杂的三维环境，具有深刻的 对发育过程中突触可塑性和髓鞘形成的影响。途径和细胞类型 在大脑发育过程中驱动ECM的产生知之甚少。该提案调查了 最近确定的细胞途径，该途径控制着少突胶质细胞祖细胞的ECM组成 细胞（OPC）。这一发现是通过对转录因子THAP1的研究进行的，即 在神经发育运动障碍中突变Dyt-Thap1（Dyt6）肌张力障碍。以前的工作 确定了THAP1在发育性髓鞘中的关键作用。少突胶质细胞中THAP1的损失 （OL）谱系会损害OPC的发展成熟的髓鞘。最近的工作已经建立 通过控制分泌的组成，THAP1在很大程度上介导了OL的分化 硫酸软骨素（CS）插科打s，一类长的无分支多糖和核心固定物 ECM，抑制OL分化。 OPC调节ECM的假设 组成是新的，转录因子THAP1及其合作伙伴yy1提供了一个 介绍在CNS开发过程中调节ECM组成的细胞机制。 拟议的研究将对ECM和髓鞘的调节建立分子理解 由thap1。 AIM 1将使用CHIP-SEQ和转录组研究来检验THAP1和 它的共调转录因子yy1通过在 区分OPC。这两个转录因子都在髓鞘中确定了角色，并引起人类 突变时肌张力障碍。 AIM 2将检验以下假设：OPC是重要的贡献者 大脑ECM的开发调节的CS-GAG组成并定义了相对贡献 其他CNS细胞类型以及THAP1在此过程中的作用。 AIM 3检验Thap1-的假设 正常运动学习需要依赖性OL成熟并定义thap1依赖性变化 在运动学习引起的ECM途径基因中。这些研究将提高我们对 神经胶质和ECM有助于CNS运动功能的机制，并将阐明如何 这些过程的破坏有助于肌张力障碍和其他神经发育的发病机理 疾病。