Oligodendrocyte Regeneration after Neonatal Hypoxia Requires FoxO1-Mediated p27^Kip1Expression

Abstract

Diffuse white matter injury (DWMI) caused by hypoxia is associated with permanent neurodevelopmental disabilities in preterm infants. The cellular and molecular mechanisms producing DWMI are poorly defined. Using a mouse model of neonatal hypoxia, we demonstrate a biphasic effect on oligodendrocyte development, resulting in hypomyelination. Oligodendrocyte death and oligodendrocyte progenitor cell (OPC) proliferation during the week after hypoxia were followed by delayed oligodendrocyte differentiation and abnormal myelination, 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.

5-Fluorouracil causes severe CNS demyelination by disruption of TCF7L2/HDAC1/HDAC2 complex in adolescent mice

“…Measurements were made on electron micrographs from the control and the experimental groups (Jablonska et al, 2012). For g-ratio analysis, EM images were imported into NIH Image J, and the external circumference of the myelin and axons was measured (Koenning et al, 2012).…”

Intranasal epidermal growth factor treatment rescues neonatal brain injury

“…Brains were sectioned and prepared in groups at the same time as previously described 38,48 . Sagittal sections of white matter were examined with a JEOL transmission electron microscope (JEM-1400), and pictures were taken with a Gatan SC1000 ORIUS CCD camera.…”

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

“…FoxO TFs appear to exert redundant effects to coordinately regulate diverse pathways to modulate neural stem cell or progenitor cell homeostasis (32,47). In a mouse model of chronic neonatal hypoxia, FoxO1 was shown to promote OPC proliferation (48). It is thus interesting to note that TGF-β signaling regulates the timing of myelination by mediating interactions between FoxO1 and Sp1, another TF that regulates OPC maturation (49).…”