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J Neurosci DOI:10.1523/JNEUROSCI.2060-12.2012

Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression.

Publication TypeJournal Article
Year of Publication2012
AuthorsJablonska, B, Scafidi, J, Aguirre, A, Vaccarino, F, Nguyen, V, Borok, E, Horvath, TL, Rowitch, DH, Gallo, V
JournalJ Neurosci
Date Published2012 Oct 17
KeywordsAnimals, Animals, Newborn, Cell Differentiation, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p27, Forkhead Box Protein O1, Forkhead Transcription Factors, Gene Expression Regulation, Developmental, Humans, Hypoxia, Brain, Infant, Infant, Newborn, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nerve Regeneration, Oligodendroglia

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.


Alternate JournalJ. Neurosci.
PubMed ID23077062
PubMed Central IDPMC3517297
Grant ListK12 NS052159 / NS / NINDS NIH HHS / United States
P01 NS062686 / NS / NINDS NIH HHS / United States
T32 HD046388 / HD / NICHD NIH HHS / United States
DP1 OD006850 / OD / NIH HHS / United States
P30 HD040677 / HD / NICHD NIH HHS / United States
K08 NS073793 / NS / NINDS NIH HHS / United States
OD006850 / OD / NIH HHS / United States
R01 NS045702 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R00 NS057944 / NS / NINDS NIH HHS / United States
R01 NS056427 / NS / NINDS NIH HHS / United States