title: c-JUN Dimerization Protein 2 (JDP2) Is a Transcriptional Repressor of Follicle-stimulating Hormone β (FSHβ) and Is Required for Preventing Premature Reproductive Senescence in Female Mice.
abstract: Follicle-stimulating hormone (FSH) regulates follicular growth and stimulates estrogen synthesis in the ovaries. FSH is a heterodimer consisting of an α subunit, also present in luteinizing hormone, and a unique β subunit, which is transcriptionally regulated by gonadotropin-releasing hormone 1 (GNRH). Because most FSH is constitutively secreted, tight transcriptional regulation is critical for maintaining FSH levels within a narrow physiological range. Previously, we reported that GNRH induces FSHβ (Fshb) transcription via induction of the AP-1 transcription factor, a heterodimer of c-FOS and c-JUN. Herein, we identify c-JUN-dimerization protein 2 (JDP2) as a novel repressor of GNRH-mediatedFshbinduction. JDP2 exhibited high basal expression and bound theFshbpromoter at an AP-1-binding site in a complex with c-JUN. GNRH treatment induced c-FOS to replace JDP2 as a c-JUN binding partner, forming transcriptionally active AP-1. Subsequently, rapid c-FOS degradation enabled reformation of the JDP2 complex.In vivostudies revealed that JDP2 null male mice have normal reproductive function, as expected from a negative regulator of the FSH hormone. Female JDP2 null mice, however, exhibited early puberty, observed as early vaginal opening, larger litters, and early reproductive senescence. JDP2 null females had increased levels of circulating FSH and higher expression of theFshbsubunit in the pituitary, resulting in elevated serum estrogen and higher numbers of large ovarian follicles. Disruption of JDP2 function therefore appears to cause early cessation of reproductive function, a condition that has been associated with elevated FSH in women.
authors.affiliation: From the Division of Biomedical Sciences, School of Medicine, University of California, Riverside, California 92521.
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Jonak
authors.affiliation: From the Division of Biomedical Sciences, School of Medicine, University of California, Riverside, California 92521.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Lainez
authors.affiliation: From the Division of Biomedical Sciences, School of Medicine, University of California, Riverside, California 92521.
authors.forename: Lacey L
authors.initials: LL
authors.lastname: Roybal
authors.affiliation: From the Division of Biomedical Sciences, School of Medicine, University of California, Riverside, California 92521.
authors.forename: Alexa D
authors.initials: AD
authors.lastname: Williamson
authors.affiliation: From the Division of Biomedical Sciences, School of Medicine, University of California, Riverside, California 92521 djurdjica.coss@ucr.edu.
authors.forename: Djurdjica
authors.initials: D
authors.lastname: Coss
mesh_terms: D000818:Animals; D005260:Female; D005640:Follicle Stimulating Hormone / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016649:Primary Ovarian Insufficiency / Q000517:prevention & control*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C491386:Jundp2 protein, mouse; D012097:Repressor Proteins; D007987:Gonadotropin-Releasing Hormone; D005640:Follicle Stimulating Hormone
keywords: AP-1 transcription factor (AP-1); c-FOS; c-JUN transcription factor; endocrinology; follicle-stimulating hormone (FSH); gene expression; gene transcription