Cholesterol Biosynthesis Defines Oligodendrocyte Precursor Heterogeneity between Brain and Spinal Cord

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 has not been identified. 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 mechanistic target of rapamycin (mTOR) as a major regulator promoting cholesterol biosynthesis in oligodendroglia. Oligodendroglial-specific loss of mTOR decreases cholesterol biosynthesis in both the brain and spinal cord. Importantly, mTOR loss has a greater impact on cholesterol biosynthesis in spinal cord oligodendroglia which corresponds with more pronounced developmental deficits. However, loss of mTOR in brain oligodendroglia ultimately results in oligodendrocyte death, spontaneous demyelination, and impaired axonal function, demonstrating that mTOR is required for myelin maintenance in the adult brain.