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Molecular and Cellular Biology, May 2005, p. 3492-3505, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3492-3505.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Orphan Nuclear Receptor LRH-1 Is Required To Maintain Oct4 Expression at the Epiblast Stage of Embryonic Development

Peili Gu,1 Bryan Goodwin,2 Arthur C.-K. Chung,1 Xueping Xu,1 David A. Wheeler,3 Roger R. Price,2 Cristin Galardi,2 Li Peng,4 Anne M. Latour,5 Beverly H. Koller,5 Jan Gossen,6 Steven A. Kliewer,4 and Austin J. Cooney1*

Department of Molecular and Cellular Biology,1 Department of Molecular and Human Genetics,3 Baylor College of Medicine, Houston, and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas Texas,4 High Throughput Biology, GlaxoSmithKline, Research Triangle Park,2 Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill North Carolina,5 Department of Pharmacology, N.V. Organon, Oss, The Netherlands6

Received 4 October 2004/ Returned for modification 11 November 2004/ Accepted 31 January 2005

Oct4 plays an essential role in maintaining the inner cell mass and pluripotence of embryonic stem (ES) cells. The expression of Oct4 is regulated by the proximal enhancer and promoter in the epiblast and by the distal enhancer and promoter at all other stages in the pluripotent cell lineage. Here we report that the orphan nuclear receptor LRH-1, which is expressed in undifferentiated ES cells, can bind to SF-1 response elements in the proximal promoter and proximal enhancer of the Oct4 gene and activate Oct4 reporter gene expression. LRH-1 is colocalized with Oct4 in the inner cell mass and the epiblast of embryos at early developmental stages. Disruption of the LRH-1 gene results in loss of Oct4 expression at the epiblast stage and early embryonic death. Using LRH-1–/– ES cells, we also show that LRH-1 is required to maintain Oct4 expression at early differentiation time points. In vitro and in vivo results show that LRH-1 plays an essential role in the maintenance of Oct4 expression in ES cells at the epiblast stage of embryonic development, thereby maintaining pluripotence at this crucial developmental stage prior to segregation of the primordial germ cell lineage at gastrulation.

* 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.

Molecular and Cellular Biology, May 2005, p. 3492-3505, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3492-3505.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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