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

摘要/项目摘要 大脑细胞外基质（ECM）是一个复杂的三维环境，具有深远的影响 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 人们对大脑发育过程中 ECM 生成的驱动知之甚少。该提案调查了 最近发现了控制少突胶质细胞祖细胞 ECM 成分的细胞途径 细胞（OPC）。这一发现是通过对转录因子 THAP1 的研究得出的，THAP1 是 神经发育运动障碍 DYT-THAP1 (DYT6) 肌张力障碍中发生突变。以前的工作 确定了 THAP1 在发育髓鞘形成中的关键作用。少突胶质细胞中 THAP1 缺失 (OL) 谱系会损害 OPC 向成熟髓鞘 OL 的进展。最近的工作已确定 THAP1 在很大程度上通过控制分泌的成分来介导 OL 分化 硫酸软骨素 (CS) GAG，一类长的无支链多糖，是硫酸软骨素的核心成分 ECM，对 OL 分化有抑制作用。 OPCs 调节 ECM 的假设 组成是新的，转录因子 THAP1 与其伙伴 YY1 一起提供了 正在努力描述中枢神经系统发育过程中调节 ECM 组成的细胞机制。 拟议的研究将建立对 ECM 和髓鞘形成调节的分子理解 由THAP1。目标 1 将使用 ChIP-seq 和转录组研究来检验 THAP1 和 其共调控转录因子 YY1 通过共享途径调节 GAG 代谢 区分 OPC。这两种转录因子都在髓鞘形成中发挥作用，并导致人类 突变时肌张力障碍。目标 2 将检验 OPC 是重要贡献者的假设 大脑 ECM 的发育调节 CS-GAG 组成并定义相对贡献 其他中枢神经系统细胞类型的作用，以及 THAP1 在此过程中的作用。目标 3 检验 THAP1- 的假设 依赖 OL 成熟是正常运动学习所必需的，并定义 THAP1 依赖的变化 运动学习诱导的 ECM 通路基因。这些研究将加深我们对 神经胶质细胞和 ECM 促进中枢神经系统运动功能的机制，并将揭示如何 这些过程的破坏导致肌张力障碍和其他神经发育障碍的发病机制 失调。

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.