THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes.
THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes.
复制标题
THAP1 通过调节溶酶体中的 ECM 降解来调节少突胶质细胞的成熟。
DOI：
10.1073/pnas.2100862118
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发表时间：
2021
影响因子：
11.1
通讯作者：
Dauer,WilliamT
中科院分区：
文献类型：
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作者：
Yellajoshyula,Dhananjay;Pappas,SamuelS;Rogers,AbigailE;Choudhury,Biswa;Reed,Xylena;Ding,Jinhui;Cookson,MarkR;Shakkottai,VikramG;Giger,RomanJ;Dauer,WilliamT
中枢神经系统成熟过程中髓鞘形成的控制机制在中枢神经系统回路的发育和完善中起着关键作用。转录因子THAP1通过在少突胶质细胞谱系中发挥细胞自主作用，对中枢神经系统成熟过程中髓鞘形成的起始时间至关重要。在这里，我们证明THAP1通过调节少突胶质细胞祖细胞（OPCs）内的糖胺聚糖（GAG）分解代谢来调节细胞外基质（ECM）组成。Thap1−/−OPCs积累和分泌过量的gag，通过自身抑制机制抑制其成熟。THAP1通过结合和调节编码β-葡萄糖醛酸酶（一种GAG分解代谢溶酶体酶）的gusb基因来控制GAG代谢。应用gag -降解酶或过表达β-葡糖醛酸酶可在体外和体内修复thap1 - / - OL成熟缺陷。我们的研究确定了OPCs内溶酶体GAG分解代谢是调节少突胶质细胞发育的关键机制。
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 theGusBgene encoding β-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing β-glucuronidase rescuesThap1−/−OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.