R‐Ras1 and R‐Ras2 regulate mature oligodendrocyte subpopulations

In the mammalian central nervous system, axonal myelination, executed by mature oligodendrocytes (MOLs), enables rapid neural transmission. Conversely, myelin deficiencies are hallmark features of multiple sclerosis, optic neuromyelitis, and some leukodystrophies. Recent studies have highlighted that MOLs are heterogeneous; however, how MOL subpopulations are specified and balanced in physiological settings is poorly understood. Previous works have demonstrated an essential role of the small GTPases R-Ras1 and R-Ras2 in the survival and myelination of oligodendrocytes. In this study, we aimed to determine how R-Ras1 and R-Ras2 contribute to the heterogeneity of MOL subpopulations. Our results evidence that R-Ras1 and R-Ras2 affect specification into the distinct subpopulations MOL1, MOL2, and MOL5/6, which in turn vary in their dependence of these GTPases. In R-Ras1 and/or R-Ras2 mutant mice, we observed an increase in the MOL1 subpopulation and a decrease in the MOL2 and MOL5/6 subpopulations. We identified R-Ras1 and R-Ras2 as key elements in balancing the heterogeneity of MOLs. Our results contribute to the understanding of the molecular mechanisms underlying the heterogeneity of MOLs and the myelination processes, which is crucial for innovating regenerative therapies for nervous system disorders.