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Brain and spinal cord oligodendroglia have distinct functional characteristics, and cell-autonomous loss of individual genes can result in different regional phenotypes. However, a molecular basis for these distinctions is unknown. Using single-cell analysis of oligodendroglia during developmental myelination, we demonstrate that brain and spinal cord precursors are transcriptionally distinct, defined predominantly by cholesterol biosynthesis. We further identify the mechanistic target of rapamycin (mTOR) as a major regulator promoting cholesterol biosynthesis in oligodendroglia. Oligodendroglia-specific loss of mTOR decreases cholesterol biosynthesis in both the brain and the spinal cord, but mTOR loss in spinal cord oligodendroglia has a greater impact on cholesterol biosynthesis, consistent with more pronounced deficits in developmental myelination. In the brain, mTOR loss results in a later adult myelin deficit, including oligodendrocyte death, spontaneous demyelination, and impaired axonal function, demonstrating that mTOR is required for myelin maintenance in the adult brain. [Display omitted] • scRNA sequencing shows distinct oligodendrocyte precursors in brain and spinal cord • Brain and spinal cord oligodendroglia differentially regulate cholesterol synthesis • mTOR is necessary for normal cholesterol biosynthesis in oligodendroglia • mTOR is necessary for myelin maintenance Using single-cell RNA sequencing, Khandker et al. reveal that oligodendroglia in the brain and spinal cord are distinct. These differences arise from mechanisms regulating cholesterol acquisition, necessary for maintenance of the lipid-rich myelin sheath, and involve mTOR in the regulation of cholesterol biosynthesis in oligodendroglia. [ABSTRACT FROM AUTHOR]