Document Detail

Oligodendrocyte regeneration after neonatal hypoxia requires FoxO1-mediated p27Kip1 expression.
MedLine Citation:
PMID:  23077062     Owner:  NLM     Status:  MEDLINE    
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.
Beata Jablonska; Joseph Scafidi; Adan Aguirre; Flora Vaccarino; Vien Nguyen; Erzsebet Borok; Tamas L Horvath; David H Rowitch; Vittorio Gallo
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  32     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-18     Completed Date:  2013-01-02     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14775-93     Citation Subset:  IM    
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MeSH Terms
Animals, Newborn
Cell Differentiation / physiology*
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis*,  genetics
Forkhead Transcription Factors / physiology*
Gene Expression Regulation, Developmental*
Hypoxia, Brain / metabolism*,  pathology
Infant, Newborn
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Nerve Regeneration / physiology*
Oligodendroglia / cytology,  physiology*
Grant Support
K08 NS073793/NS/NINDS NIH HHS; K08 NS073793/NS/NINDS NIH HHS; K12 NS052159/NS/NINDS NIH HHS; OD006850/OD/NIH HHS; P01 NS062686/NS/NINDS NIH HHS; P01 NS062686/NS/NINDS NIH HHS; P30 HD040677/HD/NICHD NIH HHS; R01 NS045702/NS/NINDS NIH HHS; R01 NS045702/NS/NINDS NIH HHS; R01 NS056427/NS/NINDS NIH HHS; T32 HD046388/HD/NICHD NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Forkhead Transcription Factors; 0/Foxo1 protein, mouse; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27
Comment In:
Regen Med. 2013 Jan;8(1):18-9   [PMID:  23390633 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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