Systemic and intrinsic functions of ATRX in glial cell fate and CNS myelination in male mice

Myelin, an extension of the oligodendrocyte plasma membrane, wraps around axons to facilitate nerve conduction. Myelination is compromised in ATR-X intellectual disability syndrome patients, but the causes are unknown. We show that loss of ATRX leads to myelination deficits in male mice that are partially rectified upon systemic thyroxine administration. Targeted ATRX inactivation in either neurons or oligodendrocyte progenitor cells (OPCs) reveals OPC-intrinsic effects on myelination. OPCs lacking ATRX fail to differentiate along the oligodendrocyte lineage and acquire a more plastic state that favors astrocytic differentiation in vitro and in vivo. ATRX chromatin occupancy in OPCs greatly overlaps with that of the chromatin remodelers CHD7 and CHD8 as well as H3K27Ac, a mark of active enhancers. Overall, our data indicate that ATRX regulates the onset of myelination systemically via thyroxine, and by promoting OPC differentiation and suppressing astrogliogenesis. These functions of ATRX identified in mice could explain white matter pathogenesis observed in ATR-X syndrome patients. Myelination is often compromised in ATR-X intellectual disability syndrome patients. Here, the authors show that the causative gene, ATRX, can regulate myelination in mice by modulating systemic thyroxine levels and by supporting oligodendrocyte progenitor differentiation.

Automated summary

The ATRX gene regulates myelination in mice by modulating systemic thyroxine levels and supporting oligodendrocyte progenitor differentiation. These findings help explain white matter pathogenesis observed in ATR-X syndrome patients.