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， 影响发育过程中突触可塑性和髓鞘形成。这些通路和细胞类型 人们对大脑发育过程中驱动ECM产生的机制知之甚少。该提案调查了 最近确定的控制来自少突胶质细胞祖细胞的ECM成分的细胞途径 细胞（OPC）。这一发现是通过对转录因子THAP 1的研究得出的， 在神经发育运动障碍DYT-THAP 1（DYT 6）肌张力障碍中突变。以前的工作 确定了THAP 1在发育髓鞘形成中的关键作用。少突胶质细胞中THAP 1的缺失 (OL)谱系损害OPC向成熟髓鞘形成OL的进展。最近的工作建立了 THAP 1在很大程度上通过控制分泌的 硫酸软骨素（CS）GAG，一类长的无分支的多糖和软骨素的核心成分， 抑制OL分化ECM。OPCs调节ECM的假说 组合物是新的，转录因子THAP 1与其伴侣YY 1一起提供了一种新的转录因子。 在描述CNS发育过程中调节ECM成分的细胞机制方面取得了进展。 这些研究将从分子水平上了解ECM和髓鞘形成的调控 THAP1。目的1将使用ChIP-seq和转录组学研究来检验THAP 1和 其共调节转录因子YY 1通过一条共享途径调节GAG代谢， 区分OPCs。这两种转录因子都在髓鞘形成中发挥作用，并导致人类 突变后的肌张力障碍目标2将检验OPCs是以下重要贡献者的假设： 发育调节的脑ECM的CS-GAG组成，并定义相对贡献 其他CNS细胞类型，以及THAP 1在这一过程中的作用。目的3检验THAP 1- 正常运动学习需要依赖性OL成熟，并定义THAP 1依赖性变化 在运动学习诱导的ECM通路基因中。这些研究将促进我们对 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，并将揭示如何 这些过程的中断有助于肌张力障碍和其他神经发育障碍的发病机制。 紊乱

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.