Oligodendrocyte regeneration after neonatal hypoxia requires FoXo1-mediated p27^kip1 expression

Diffuse whitematter injury (DWMI) causedbyhypoxiaisassociated withpermanent neurodevelopmental disabilitiesinpreterm infants. The cellular and molecular mechanisms producing DWMI are poorly defined. Usingamouse modelofneonatal hypoxia,wedemonstrate a biphasic effectonoligodendrocyte development, resultinginhypomyelination. Oligodendrocyte death and oligodendrocyte progenitor cell (OPC) proliferation during the week after hypoxia were followed by delayed oligodendrocyte differentiation and abnormal myelina-tion, as demonstrated by electron microscopy. Cdk2 activation was essential for the regenerative OPC response after hypoxia and was accompanied by reduced FoxO1-dependent p27^Kip1 expression. p27^Kip1 was also reduced in OPCs in human infant white matter lesions after hypoxia. The negative effects of hypoxia on oligodendrogenesis and myelination were more pronounced in p27^Kip1-null mice; conversely, overexpression of FoxO1 or p27^Kip1 in OPCs after hypoxia promoted oligodendrogenesis. Our studies demonstrate for the first time that neonatal hypoxia affects the Foxo1/p27^Kip1 pathway during white matter development. We also show that molecular manipulation of this pathway enhances oligodendrocyte regeneration during a critical developmental time window after DWMI. Thus, FoxO1 and p27^Kip1 may serve as promising target molecules for promoting timely oligodendrogenesis in neonatal DWMI.