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

摘要/项目摘要 脑细胞外基质(ECM)是一个复杂的三维环境，具有深刻的 发育过程中对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细胞外基质生成的机制还知之甚少。这项提案调查了一个 最近发现的控制少突胶质细胞前体细胞ECM组成的细胞途径 细胞(OPC)。这一发现是通过对转录因子THAP1的研究得出的，THAP1是 在神经发育运动障碍Dyt-THAP1(DYT6)肌张力障碍中突变。以前的工作 确定了THAP1在发育髓鞘形成中的关键作用。THAP1在少突胶质细胞中的丢失 (OL)谱系损害OPC向成熟的髓鞘OL的进展。最近的研究已经确立了 THAP1在很大程度上通过控制分泌物的成分来介导OL的分化 硫酸软骨素(CS)是一类长链多糖，其核心成分为硫酸软骨素。 对OL分化有抑制作用的细胞外基质。OPC调控ECM的假说 组成是新的，转录因子THAP1与其伴侣YY1一起提供了一种 揭示在中枢神经系统发育过程中调节细胞外基质成分的细胞机制。 拟议的研究将建立对细胞外基质和髓鞘形成调节的分子理解。 通过THAP1。Aim 1将使用CHIP-SEQ和转录转录研究来检验THAP1和THAP1 其共调控转录因子YY1通过共同的途径调节GAG代谢。 区分OPC。这两种转录因子都在髓鞘形成过程中发挥了作用，并导致人类 肌张力障碍当突变时。目标2将检验OPC是重要贡献者的假设 发育调节的脑细胞外基质CS-GAG组成及其相对贡献 以及THAP1在这一过程中的作用。目的3检验假设THAP1- 依赖的OL成熟是正常运动学习和定义THAP1依赖的变化所必需的 在运动学习诱导的ECM通路基因中。这些研究将增进我们对 胶质细胞和细胞外基质促进中枢神经系统运动功能的机制，并将阐明如何 这些过程的中断导致肌张力障碍和其他神经发育障碍的发病 精神错乱。

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.