Erythropoietin regulates developmental myelination in the brain stimulating postnatal oligodendrocyte maturation

Myelination is a process that is tightly regulated by a variety of neurotrophic factors. Here, we show - by analyzing two transgenic mouse lines, one overexpressing EPO selectively in the brain Tg21 ( PDGFB-rhEPO ), and another with targeted removal of EPO receptors (EPORs) from oligodendrocyte progenitor cells (OPC)s ( Sox10-cre;EPOR fl/fl mice ) – a key function for EPO in regulating developmental brain myelination. Overexpression of EPO resulted in faster postnatal brain growth and myelination, an increased number of myelinating oligodendrocytes, faster axonal myelin ensheathment, and improved motor coordination. Inversely, targeted ablation of EPORs from OPCs reduced the number of mature oligodendrocytes and impaired motor coordination during the second postnatal week. Further, we found that EPORs are transiently expressed in the subventricular zone (SVZ) during the second postnatal week, and they stimulate the Erk1/2 pathway as well as the expression of essential oligodendrocyte pro-differentiation and pro-maturation transcripts (Nkx6.2 and Myrf), and the Nfatc2/calcineurin pathway. Our results reveal developmental time windows in which EPORs are expressed when therapies could be highly effective for stimulating oligodendrocyte maturation and myelination.