title: Core Binding Factor-β Knockdown Alters Ovarian Gene Expression and Function in the Mouse.
abstract: Core binding factor (CBF) is a heterodimeric transcription factor complex composed of a DNA-binding subunit, one of three runt-related transcription factor (RUNX) factors, and a non-DNA binding subunit, CBFβ. CBFβ is critical for DNA binding and stability of the CBF transcription factor complex. In the ovary, the LH surge increases the expression of Runx1 and Runx2 in periovulatory follicles, implicating a role for CBFs in the periovulatory process. The present study investigated the functional significance of CBFs (RUNX1/CBFβ and RUNX2/CBFβ) in the ovary by examining the ovarian phenotype of granulosa cell-specific CBFβ knockdown mice; CBFβ f/f * Cyp19 cre. The mutant female mice exhibited significant reductions in fertility, with smaller litter sizes, decreased progesterone during gestation, and fewer cumulus oocyte complexes collected after an induced superovulation. RNA sequencing and transcriptome assembly revealed altered expression of more than 200 mRNA transcripts in the granulosa cells of Cbfb knockdown mice after human chorionic gonadotropin stimulation in vitro. Among the affected transcripts are known regulators of ovulation and luteinization including Sfrp4, Sgk1, Lhcgr, Prlr, Wnt4, and Edn2 as well as many genes not yet characterized in the ovary. Cbfβ knockdown mice also exhibited decreased expression of key genes within the corpora lutea and morphological changes in the ovarian structure, including the presence of large antral follicles well into the luteal phase. Overall, these data suggest a role for CBFs as significant regulators of gene expression, ovulatory processes, and luteal development in the ovary.
authors.affiliation: Department of Obstetrics and Gynecology (K.W., J.P., T.E.C., B.M., M.J.), Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0298; Women's Health Department (J.G.), Merck Sharp and Dohme Research Laboratories, 5340-BH Oss, The Netherlands; and Laboratory for Transcriptional Regulation (I.T.), Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Kalin
authors.initials: K
authors.lastname: Wilson
authors.affiliation: Department of Obstetrics and Gynecology (K.W., J.P., T.E.C., B.M., M.J.), Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0298; Women's Health Department (J.G.), Merck Sharp and Dohme Research Laboratories, 5340-BH Oss, The Netherlands; and Laboratory for Transcriptional Regulation (I.T.), Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Obstetrics and Gynecology (K.W., J.P., T.E.C., B.M., M.J.), Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0298; Women's Health Department (J.G.), Merck Sharp and Dohme Research Laboratories, 5340-BH Oss, The Netherlands; and Laboratory for Transcriptional Regulation (I.T.), Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Curry
authors.affiliation: Department of Obstetrics and Gynecology (K.W., J.P., T.E.C., B.M., M.J.), Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0298; Women's Health Department (J.G.), Merck Sharp and Dohme Research Laboratories, 5340-BH Oss, The Netherlands; and Laboratory for Transcriptional Regulation (I.T.), Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Birendra
authors.initials: B
authors.lastname: Mishra
authors.affiliation: Department of Obstetrics and Gynecology (K.W., J.P., T.E.C., B.M., M.J.), Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0298; Women's Health Department (J.G.), Merck Sharp and Dohme Research Laboratories, 5340-BH Oss, The Netherlands; and Laboratory for Transcriptional Regulation (I.T.), Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Jan
authors.initials: J
authors.lastname: Gossen
authors.affiliation: Department of Obstetrics and Gynecology (K.W., J.P., T.E.C., B.M., M.J.), Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0298; Women's Health Department (J.G.), Merck Sharp and Dohme Research Laboratories, 5340-BH Oss, The Netherlands; and Laboratory for Transcriptional Regulation (I.T.), Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Taniuchi
authors.affiliation: Department of Obstetrics and Gynecology (K.W., J.P., T.E.C., B.M., M.J.), Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0298; Women's Health Department (J.G.), Merck Sharp and Dohme Research Laboratories, 5340-BH Oss, The Netherlands; and Laboratory for Transcriptional Regulation (I.T.), Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Misung
authors.initials: M
authors.lastname: Jo
mesh_terms: D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D050657:Core Binding Factor alpha Subunits / Q000235:genetics / Q000378:metabolism; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000378:metabolism*; D003338:Corpus Luteum / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006107:Granulosa Cells / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D034461:Luteinization / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000378:metabolism; D010053:Ovary / Q000378:metabolism*; D010060:Ovulation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D060528:Wnt4 Protein / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D006063:Chorionic Gonadotropin; D050659:Core Binding Factor Alpha 1 Subunit; D050676:Core Binding Factor Alpha 2 Subunit; D050657:Core Binding Factor alpha Subunits; D050658:Core Binding Factor beta Subunit; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D060528:Wnt4 Protein; D000099184:Serum-Glucocorticoid Regulated Kinases; C498454:Sfrp4 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C555582:Wnt4 protein, mouse