Peroxisome proliferator-activated receptor gamma is a target of progesterone regulation in the preovulatory follicles and controls ovulation in mice.
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 gamma (PPARgamma) as a target of regulation by PR in the granulosa cells of the preovulatory follicles during the ovulatory process. To investigate the function of PPARgamma 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 PPARgamma in the ovary. Our studies also suggested that cycloxygenase 2-derived metabolites of long-chain fatty acids function as endogenous activating ligands of PPARgamma in the preovulatory follicles. Collectively, these studies revealed that PPARgamma is a key mediator of the biological actions of PR in the granulosa cells and activation of its downstream pathways critically controls ovulation.
Kim
Jaeyeon
J
University of Illinois, MC-114, 534 Burrill Hall, 407 S. Goodwin, Urbana, IL 61801, USA.
Sato
Marcey
M
Li
Quanxi
Q
Lydon
John P
JP
Demayo
Francesco J
FJ
Bagchi
Indrani C
IC
Bagchi
Milan K
MK
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006062:Gonadotropins / Q000494:pharmacology; D006107:Granulosa Cells / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D015735:Mifepristone / Q000494:pharmacology; D008957:Models, Genetic; D009578:Nitrobenzenes / Q000494:pharmacology; D006080:Ovarian Follicle / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D010060:Ovulation / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011374:Progesterone / Q000502:physiology*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016895:Culture Media, Serum-Free; D006062:Gonadotropins; D006727:Hormone Antagonists; D009578:Nitrobenzenes; D047495:PPAR gamma; D011980:Receptors, Progesterone; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D005576:Colforsin; D015735:Mifepristone; D011374:Progesterone; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin