Defective oligodendrocyte development and function in an RNA polymerase III mutant leukodystrophic mouse

RNA polymerase (Pol) III synthesizes abundant short non-coding RNAs that have essential functions in protein synthesis, secretion and other processes. Despite the ubiquitous functions of these RNAs, mutations in Pol III subunits cause Pol III-related leukodystrophy, an early-onset neurodegenerative disease. The basis of this neural sensitivity and the mechanisms of disease pathogenesis are unknown. Here we show that mice expressing pathogenic mutations in the largest Pol III subunit, Polr3a, specifically in Olig2-expressing cells, have impaired growth, neurobehavioral deficits and hypomyelination in multiple regions of the brain and spinal cord. We identify two mechanisms of disease pathogenesis within the oligodendrocyte (OL) lineage; a differentiation defect of oligodendrocyte precursor cells reduces the number of mature myelinating OLs and an intrinsic myelination defect in mature OLs impairs myelin deposition. Thus, we reveal cell-specific roles for Pol III in the normal development and function of oligodendrocytes.