title: Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice.
abstract: Impairments in pituitary FSH synthesis or action cause infertility. However, causes of FSH dysregulation are poorly described, in part because of our incomplete understanding of mechanisms controlling FSH synthesis. Previously, we discovered a critical role for forkhead protein L2 (FOXL2) in activin-stimulated FSH β-subunit (Fshb) transcription in immortalized cells in vitro. Here, we tested the hypothesis that FOXL2 is required for FSH synthesis in vivo. Using a Cre/lox approach, we selectively ablated Foxl2 in murine anterior pituitary gonadotrope cells. Conditional knockout (cKO) mice developed overtly normally but were subfertile in adulthood. Testis size and spermatogenesis were significantly impaired in cKO males. cKO females exhibited reduced ovarian weight and ovulated fewer oocytes in natural estrous cycles compared with controls. In contrast, ovaries of juvenile cKO females showed normal responses to exogenous gonadotropin stimulation. Both male and female cKO mice were FSH deficient, secondary to diminished pituitary Fshb mRNA production. Basal and activin-stimulated Fshb expression was similarly impaired in Foxl2 depleted primary pituitary cultures. Collectively, these data definitively establish FOXL2 as the first identified gonadotrope-restricted transcription factor required for selective FSH synthesis in vivo.
authors: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors: Stella
authors: S
authors: Tran
authors: Xiang
authors: X
authors: Zhou
authors: Christine
authors: C
authors: Lafleur
authors: Michael J
authors: MJ
authors: Calderon
authors: Buffy S
authors: BS
authors: Ellsworth
authors: Sarah
authors: S
authors: Kimmins
authors: Ulrich
authors: U
authors: Boehm
authors: Mathias
authors: M
authors: Treier
authors: Derek
authors: D
authors: Boerboom
authors: Daniel J
authors: DJ
authors: Bernard
mesh_terms: D028341:Activins / Q000494:pharmacology; D000818:Animals; D005260:Female; D005298:Fertility; D037201:Follicle Stimulating Hormone, beta Subunit / Q000096:biosynthesis* / Q000172:deficiency; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D056426:Genetic Loci / Q000235:genetics; D052681:Gonadotrophs / Q000187:drug effects / Q000378:metabolism*; D006062:Gonadotropins / Q000097:blood; D006736:Horses; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000502:physiology; D010060:Ovulation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D012708:Sertoli Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D037201:Follicle Stimulating Hormone, beta Subunit; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D006062:Gonadotropins; D012333:RNA, Messenger; C422405:activin A; D028341:Activins