Choline transporters are required for oligodendrocyte differentiation and myelin sheath formation in mouse postnatal brain

Oligodendrocyte (OL) myelination is essential for neurological function in the brain. During OL differentiation, rapid membrane synthesis is required for myelin formation, but the mechanisms driving this process remain poorly understood. Choline, a critical component of membrane phospholipids, is transported into cells via choline transporters (ChTs). Here, we identify SLC44A1 and SLC44A5 as the predominant ChTs selectively expressed in oligodendroglia. Conditional knockout (cKO) of either SLC44A1 or SLC44A5 in oligodendroglia impairs OL differentiation and myelination in neonatal brains, with shortened myelin segment lengths. SLC44A1-cKO mice show persistent hypomyelination into adulthood whereas SLC44A5-cKO mice do not, a divergence likely attributable to age-related decline in SLC44A5 expression in oligodendroglia. Metabolomics profiling indicates disrupted lipid metabolism by SLC44A1 deletion, specifically inhibiting plasmalogen synthesis, a pathway vital for myelin biogenesis. Our findings show that SLC44A1/5 support white matter integrity by fueling lipid metabolism, underscoring their potential as therapeutic targets for demyelinating diseases.