GATA4 and GATA6 Knockdown During Luteinization Inhibits Progesterone Production and Gonadotropin Responsiveness in the Corpus Luteum of Female Mice.
The surge of luteinizing hormone triggers the genomic reprogramming, cell differentiation, and tissue remodeling of the ovulated follicle, leading to the formation of the corpus luteum. During this process, called luteinization, follicular granulosa cells begin expressing a new set of genes that allow the resulting luteal cells to survive in a vastly different hormonal environment and to produce the extremely high amounts of progesterone (P4) needed to sustain pregnancy. To better understand the molecular mechanisms involved in the regulation of luteal P4 production in vivo, the transcription factors GATA4 and GATA6 were knocked down in the corpus luteum by crossing mice carrying Gata4 and Gata6 floxed genes with mice carrying Cre recombinase fused to the progesterone receptor. This receptor is expressed exclusively in granulosa cells after the luteinizing hormone surge, leading to recombination of floxed genes during follicle luteinization. The findings demonstrated that GATA4 and GATA6 are essential for female fertility, whereas targeting either factor alone causes subfertility. When compared to control mice, serum P4 levels and luteal expression of key steroidogenic genes were significantly lower in conditional knockdown mice. The results also showed that GATA4 and GATA6 are required for the expression of the receptors for prolactin and luteinizing hormone, the main luteotropic hormones in mice. The findings demonstrate that GATA4 and GATA6 are crucial regulators of luteal steroidogenesis and are required for the normal response of luteal cells to luteotropins.
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
Scott M
SM
Convissar
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
Jill
J
Bennett
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
Sarah C
SC
Baumgarten
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
John P
JP
Lydon
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Francesco J
FJ
DeMayo
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois costocco@uic.edu.
Carlos
C
Stocco
D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003338:Corpus Luteum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D007247:Infertility, Female / Q000235:genetics* / Q000378:metabolism; D034461:Luteinization / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D011374:Progesterone / Q000096:biosynthesis*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism
D006063:Chorionic Gonadotropin; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C484171:Gata4 protein, mouse; C494760:Gata6 protein, mouse; D011980:Receptors, Progesterone; D011374:Progesterone
GATA; corpus luteum; female infertility; luteinizing hormone (LH/LH receptor); progesterone/progesterone receptor