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

Abstract

Neurodevelopmental disorders are often characterized by abnormal production of myelin, an extension of the oligodendrocyte plasma membrane wrapped around axons to facilitate nerve conduction. However, the molecular mechanisms that control myelination during brain development are incompletely resolved. Here, we provide evidence that loss of ATRX, encoded by the gene mutated in the ATR-X intellectual disability syndrome, leads to myelin deficits in the mouse CNS. While postnatal systemic thyroxine administration can improve myelination, the rescue is incomplete, pointing to additional roles of ATRX in this process. We show that targeted inactivation of ATRX in postnatal oligodendrocyte progenitor cells (OPCs), but not in neurons, also leads to myelination deficits, demonstrating cell-intrinsic effects of ATRX deficiency. A subset of ATRX-null OPCs express lower levels of oligodendrocyte specification and differentiation markers, including the basic helix-loop-helix Olig2 transcription factor. Mechanistically, we provide evidence that ATRX occupies genomic sites in OPCs marked by H3K27Ac, CHD7 and CHD8 and demonstrate that reduced Olig2 expression is associated with decreased H3K27Ac. Finally, our data suggest that ATRX-null OPCs acquire a more plastic state and can exhibit astrocyte-like features in vitro and in vivo, supporting a model in which ATRX regulates the onset of myelination by promoting OPC identity and suppressing astrogliogenesis. These previously unrecognized functions of ATRX might explain white matter pathogenesis in ATR-X syndrome patients.