Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during retinoic acid-induced embryonic stem cell differentiation.

TitleOrphan nuclear receptor GCNF is required for the repression of pluripotency genes during retinoic acid-induced embryonic stem cell differentiation.
Publication TypeJournal Article
Year of Publication2005
AuthorsGu, P, LeMenuet, D, Chung, AC-K, Mancini, M, Wheeler, DA, Cooney, AJ
JournalMol Cell Biol
Volume25
Issue19
Pagination8507-19
Date Published2005 Oct
ISSN0270-7306
KeywordsAnimals, Blotting, Northern, Blotting, Western, Cell Differentiation, Cell Line, Cell Nucleus, Chromatin Immunoprecipitation, DNA-Binding Proteins, Down-Regulation, Embryo, Mammalian, Female, Fibroblast Growth Factor 4, Genotype, Homeodomain Proteins, In Situ Hybridization, Male, Mice, Mice, Transgenic, Microscopy, Fluorescence, Models, Genetic, Nanog Homeobox Protein, Nuclear Receptor Subfamily 6, Group A, Member 1, Octamer Transcription Factor-3, Phenotype, Plasmids, Protein Binding, Receptors, Cytoplasmic and Nuclear, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, SOXB1 Transcription Factors, Stem Cells, Time Factors, Trans-Activators, Transfection, Tretinoin
Abstract

Embryonic stem (ES) cell pluripotency and differentiation are controlled by a network of transcription factors and signaling molecules. Transcription factors such as Oct4 and Nanog are required for self-renewal and maintain the undifferentiated state of ES cells. Decreases in the expression of these factors indicate the initiation of differentiation of ES cells. Inactivation of the gene encoding the orphan nuclear receptor GCNF showed that it plays an important role in the repression of Oct4 expression in somatic cells during early embryonic development. GCNF-/- ES cells were isolated to study the function of GCNF in the down-regulation of pluripotency genes during differentiation. Loss of repression of ES cell marker genes Oct4, Nanog, Sox2, FGF4, and Stella was observed upon treatment of GCNF-/- ES cells with retinoic acid. The loss of repression of pluripotency genes is either a direct or indirect consequence of loss of GCNF. Both the Oct4 and Nanog genes are direct targets of GCNF repression during ES cell differentiation and early mouse embryonic development. In contrast Sox2 and FGF4 are indirectly regulated by GCNF through Oct4. These findings establish a central role for GCNF in the repression of pluripotency gene expression during retinoic acid-induced ES cell differentiation.
DOI10.1128/MCB.25.19.8507-8519.2005
Alternate JournalMol Cell Biol
PubMed ID16166633
PubMed Central IDPMC1265758
Grant ListR01 DK073524 / DK / NIDDK NIH HHS / United States
U54 HD007495 / HD / NICHD NIH HHS / United States
R01 DK73524 / DK / NIDDK NIH HHS / United States
U54 HD07495 / HD / NICHD NIH HHS / United States

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