THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes
Dhananjay Yellajoshyula, Samuel S. Pappas, Abigail Rogers, Biswa Choudhury, Xylena Reed, Jinhui Ding, Mark Cookson, Vikram G. Shakkottai, Roman J. Giger, William T. Dauer
Abstract
Significance The development and function of the nervous system is profoundly influenced by the interactions of neurons with glial cells and the extracellular matrix (ECM). Mechanisms regulating the maturation of oligodendroglial progenitor cells (OPCs) into myelinating cells to facilitate central nervous system myelination play an essential role in circuit plasticity, including motor learning. Our work has identified that THAP1, a transcription factor whose loss of function leads to the neurodevelopmental movement disorder DYT6 dystonia, drives OPC development by regulating the breakdown of glycosaminoglycans (GAGs), essential components of the ECM. GAGs produced and secreted by OPCs act in an autocrine fashion to inhibit their lineage progression, highlighting a unique mechanism regulating the pool of mature oligodendrocytes.