Oligodendrocyte regeneration after neonatal hypoxia requires FoXo1-mediated p27kip1 expression

Abstract

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 p27Kip1 expression. p27Kip1 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 p27Kip1-null mice; conversely, overexpression of FoxO1 or p27Kip1 in OPCs after hypoxia promoted oligodendrogenesis. Our studies demonstrate for the first time that neonatal hypoxia affects the Foxo1/p27Kip1 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 p27Kip1 may serve as promising target molecules for promoting timely oligodendrogenesis in neonatal DWMI. © 2012 the authors.