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Molecular and Cellular Biology, October 2005, p. 8507-8519, Vol. 25, No. 19
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.19.8507-8519.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Orphan Nuclear Receptor GCNF Is Required for the Repression of Pluripotency Genes during Retinoic Acid-Induced Embryonic Stem Cell Differentiation

Peili Gu,1,{dagger} Damien LeMenuet,1,{dagger} Arthur C.-K. Chung,1 Michael Mancini,1 David A. Wheeler,2 and Austin J. Cooney1*

Department of Molecular and Cellular Biology,1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 770302

Received 12 May 2005/ Returned for modification 9 June 2005/ Accepted 14 July 2005

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.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6250. Fax: (713) 790-1275. E-mail: acooney{at}bcm.tmc.edu.

{dagger} Contributed equally.

Molecular and Cellular Biology, October 2005, p. 8507-8519, Vol. 25, No. 19
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.19.8507-8519.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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