Mechanisms controlling myelination during central nervous system (CNS) maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates the extracellular matrix (ECM) composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1^−/− OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an autoinhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding β-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing β-glucuronidase rescues Thap1^−/− OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.

在中枢神经系统 (CNS) 成熟过程中控制髓鞘形成的机制在 CNS 电路的发展和完善中发挥着关键作用。转录因子 THAP1 通过在少突胶质细胞谱系中的细胞自主作用，对于在中枢神经系统成熟过程中计时髓鞘形成的开始至关重要。在这里，我们证明 THAP1 通过调节少突胶质祖细胞 (OPCs) 内的糖胺聚糖 (GAG) 分解代谢来调节细胞外基质 (ECM) 的组成。Thap1 ^-/- OPCs 积累和分泌过量的 GAG，通过一种自身抑制机制抑制它们的成熟。THAP1 通过结合和调节 GusB 来控制 GAG代谢编码β-葡萄糖醛酸酶的基因，一种GAG-分解代谢溶酶体酶。应用 GAG 降解酶或过表达 β-葡萄糖醛酸酶可在体外和体内挽救Thap1 ^{-/- OL 成熟缺陷。}我们的研究确定 OPCs 内的溶酶体 GAG 分解代谢是调节少突胶质细胞发育的关键机制。