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Molecular and Cellular Biology, March 2008, p. 1770-1782, Vol. 28, No. 5
0270-7306/08/$08.00+0 doi:10.1128/MCB.01556-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Is a Target of Progesterone Regulation in the Preovulatory Follicles and Controls Ovulation in Mice
Departments of Molecular and Integrative Physiology,1 Veterinary Biosciences, University of Illinois Urbana-Champaign, Urbana, Illinois,2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas3
Received 24 August 2007/ Returned for modification 4 October 2007/ Accepted 24 December 2007
The progesterone receptor (PR) plays a critical role during ovulation. Mice lacking the PR gene are anovulatory due to a failure in the rupture of the preovulatory follicles. The pathways that operate downstream of PR to control ovulation are poorly understood. Using gene expression profiling, we identified peroxisome proliferator-activated receptor
(PPAR
) as a target of regulation by PR in the granulosa cells of the preovulatory follicles during the ovulatory process. To investigate the function of PPAR
during ovulation, we created a conditional knockout mouse in which this gene was deleted via Cre-Lox-mediated excision in granulosa cells. When these mutant mice were subjected to gonadotropin-induced superovulation, the preovulatory follicles failed to rupture and the number of eggs released from the mutant ovaries declined drastically. Gene expression analysis identified endothelin-2, interleukin-6, and cyclic GMP-dependent protein kinase II as novel targets of regulation by PPAR
in the ovary. Our studies also suggested that cycloxygenase 2-derived metabolites of long-chain fatty acids function as endogenous activating ligands of PPAR
in the preovulatory follicles. Collectively, these studies revealed that PPAR
is a key mediator of the biological actions of PR in the granulosa cells and activation of its downstream pathways critically controls ovulation.
Published ahead of print on 2 January 2008.
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