Document Detail

Suppression of Oct4 by germ cell nuclear factor restricts pluripotency and promotes neural stem cell development in the early neural lineage.
MedLine Citation:
PMID:  19228964     Owner:  NLM     Status:  MEDLINE    
The earliest murine neural stem cells are leukemia inhibitory factor (LIF)-dependent, primitive neural stem cells, which can be isolated from embryonic stem cells or early embryos. These primitive neural stem cells have the ability to differentiate to non-neural tissues and transition into FGF2-dependent, definitive neural stem cells between embryonic day 7.5 and 8.5 in vivo, accompanied by a decrease in non-neural competency. We found that Oct4 is expressed in LIF-dependent primitive neural stem cells and suppressed in FGF-dependent definitive neural stem cells. In mice lacking germ cell nuclear factor (GCNF), a transcriptional repressor of Oct4, generation of definitive neural stem cells was dramatically suppressed, accompanied by a sustained expression of Oct4 in the early neuroectoderm. Knockdown of Oct4 in GCNF(-/-) neural stem cells rescued the GCNF(-/-) phenotype. Overexpression of Oct4 blocked the differentiation of primitive to definitive neural stem cells, but did not induce the dedifferentiation of definitive to primitive neural stem cells. These results suggested that primitive neural stem cells develop into definitive neural stem cells by means of GCNF induced suppression of Oct4. The Oct4 promoter was methylated during the development from primitive neural stem cell to definitive neural stem cell, while these neural stem cells lose their pluripotency through a GCNF dependent mechanism. Thus, the suppression of Oct4 by GCNF is important for the transition from primitive to definitive neural stem cells and restriction of the non-neural competency in the early neural stem cell lineage.
Wado Akamatsu; Brian DeVeale; Hideyuki Okano; Austin J Cooney; Derek van der Kooy
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  29     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-02-20     Completed Date:  2009-04-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2113-24     Citation Subset:  IM    
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S3E1.
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MeSH Terms
Cell Differentiation / genetics
Cell Lineage / genetics*
Cells, Cultured
DNA-Binding Proteins / genetics,  metabolism*
Down-Regulation / genetics
Ectoderm / cytology,  embryology
Gene Expression Regulation, Developmental / genetics
Mice, Inbred C57BL
Mice, Knockout
Nervous System / cytology,  embryology*
Neural Tube / cytology,  embryology
Neurogenesis / genetics*
Nuclear Receptor Subfamily 6, Group A, Member 1
Octamer Transcription Factor-3 / genetics,  metabolism*
Pluripotent Stem Cells / cytology,  metabolism*
Receptors, Cytoplasmic and Nuclear / genetics,  metabolism*
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Nr6a1 protein, mouse; 0/Nuclear Receptor Subfamily 6, Group A, Member 1; 0/Octamer Transcription Factor-3; 0/Pou5f1 protein, mouse; 0/Receptors, Cytoplasmic and Nuclear

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