title: Mouse forkhead L2 maintains repression of FSH-dependent genes in the granulosa cell.
abstract: The forkhead transcription factor forkhead box L2 (FOXL2) is expressed in granulosa cells of small and medium follicles in the mouse ovary. Foxl2 female knockout mice exhibit primordial follicle depletion and primary ovarian failure, but evidence from adult female conditional Foxl2 knockout mice suggests that FOXL2 may also play a significant role in maintenance of ovarian differentiation at stages beyond the primordial follicle and initial wave of folliculogenesis. We previously showed that human FOXL2 functions as a transcriptional repressor of several key genes involved in granulosa cell proliferation and differentiation, including steroidogenic acute regulatory protein (STAR), P450aromatase (CYP19A1 (CYP19)), P450scc (CYP11A1 (CYP11A)), and cyclin D2 (CCND2). To elucidate the role of mouse FOXL2, we determined its role in transcriptional regulation in Chinese hamster ovary (CHO) cells and then confirmed our findings in mouse granulosa cells. We found that mouse FOXL2 represses the activities of the mouse Star, Cyp19a1, Cyp11a1 promoters in CHO cells, but may not repress the Ccnd2 promoter, and identified the minimal mouse Star, Cyp19a1, and Cyp11a1 promoter regions responsive to FOXL2 regulation. We then knocked down Foxl2 in mouse granulosa cells using siRNA, which resulted in significantly increased expression levels of mouse Star, Cyp19a1, and Cyp11a1 but not Ccnd2. To increase Foxl2 expression levels, we generated a mouse Foxl2 lentiviral construct and used it to infect mouse granulosa cells. Following lentiviral infection, the expression levels of mouse Star, Cyp19a1, and Cyp11a1, but not Ccnd2, decreased significantly. These data confirm that mouse FOXL2 functions as a transcriptional repressor of key granulosa cell genes that influence ovarian development.
authors: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics/Gynecology, Center for Fertility and Reproductive Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Fang-Ting
authors: FT
authors: Kuo
authors: Kenneth
authors: K
authors: Fan
authors: Ikuko
authors: I
authors: Bentsi-Barnes
authors: Gillian M
authors: GM
authors: Barlow
authors: Margareta D
authors: MD
authors: Pisarska
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D021461:Animals, Outbred Strains; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D000728:Androgens; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000098682:Steroidogenic Acute Regulatory Protein; D013739:Testosterone; D005640:Follicle Stimulating Hormone; D001141:Aromatase; D002786:Cholesterol Side-Chain Cleavage Enzyme