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 GAGdegrading 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.
|Original language||English (US)|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Aug 3 2021|
- CNS myelination
- Extracellular matrix
- Neurodevelopmental disease
ASJC Scopus subject areas