The environment rules: spatiotemporal regulation of oligodendrocyte differentiation

•OPC differentiation is largely initiated by extrinsic signals.•The majority of extrinsic signals that regulate OPC differentiation are inhibitory.•Extrinsic differentiation cues include mechanical deformation of the cell membrane.•Overcoming extrinsic inhibitory cues is crucial for the repair of myelin lesions.

During development oligodendrocyte precursor cells (OPCs) rapidly proliferate and migrate throughout the central nervous system. The mobilization of OPCs is followed by terminal differentiation into mature oligodendrocytes and the subsequent myelination of axons. Differentiation of OPCs is CNS-wide and robust, and yet spatially and temporally restricted. What factors control this precise and coordinated differentiation effort? We discuss evidence for both intrinsic and extrinsic cues in regulating OPC differentiation and gather that extrinsic cues play the leading role in regulating the differentiation of OPCs into mature oligodendrocytes.