Genetic targeting of premyelinating oligodendrocytes reveals activity-dependent myelination mechanisms

To myelinate axons, oligodendrocyte precursor cells (OPCs) must stop dividing and differentiate into premyelinating oligodendrocytes (preOLs), a transient cell stage during myelination that is often stalled at human demyelinating lesions. PreOLs extend processes, surveying nearby axons to begin ensheathment. The lack of genetic tools to visualize and manipulate preOLs has hindered their in-depth study. Here we present a CreER^T2 knockin mouse line that enables genetic labeling, lineage tracing, manipulation and multimodal profiling of preOL subsets across the central nervous system. Genetically labeled preOLs are postmitotic, with distinct morphology and unique transcriptomic, epigenetic and electrophysiological features. PreOL lineage tracing revealed spatiotemporal dynamics of oligodendrogenesis across the mouse brain. Moreover, fate mapping of preOLs under sensory deprivation revealed that neuronal activity influences preOLs within a narrow maturation window, promoting their survival and successful integration. Together, our work presents a genetic tool to study preOL biology and axon-oligodendrocyte interactions in health and disease.