title: SMAD3 Regulates Follicle-stimulating Hormone Synthesis by Pituitary Gonadotrope Cellsin Vivo.
abstract: Pituitary follicle-stimulating hormone (FSH) is an essential regulator of fertility in females and of quantitatively normal spermatogenesis in males. Pituitary-derived activins are thought to act as major stimulators of FSH synthesis by gonadotrope cells.In vitro, activins signal via SMAD3, SMAD4, and forkhead box L2 (FOXL2) to regulate transcription of the FSHβ subunit gene (Fshb). Consistent with this model, gonadotrope-specificSmad4orFoxl2knock-out mice have greatly reduced FSH and are subfertile. The role of SMAD3in vivois unresolved; however, residual FSH production inSmad4conditional knock-out mice may derive from partial compensation by SMAD3 and its ability to bind DNA in the absence of SMAD4. To test this hypothesis and determine the role of SMAD3 in FSH biosynthesis, we generated mice lacking both the SMAD3 DNA binding domain and SMAD4 specifically in gonadotropes. Conditional knock-out females were hypogonadal, acyclic, and sterile and had thread-like uteri; their ovaries lacked antral follicles and corpora lutea. Knock-out males were fertile but had reduced testis weights and epididymal sperm counts. These phenotypes were consistent with those ofFshbknock-out mice. Indeed, pituitaryFshbmRNA levels were nearly undetectable in both male and female knock-outs. In contrast, gonadotropin-releasing hormone receptor mRNA levels were significantly elevated in knock-outs in both sexes. Interestingly, luteinizing hormone production was altered in a sex-specific fashion. Overall, our analyses demonstrate that SMAD3 is required for FSH synthesisin vivo.
authors.affiliation: From the Centre for Research in Reproduction and Development, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Yining
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Centre for Research in Reproduction and Development, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Gauthier
authors.initials: G
authors.lastname: Schang
authors.affiliation: the Department of Pharmacology and Toxicology, University of Saarland School of Medicine, D-66421 Homburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Boehm
authors.affiliation: the Faculty of Health Sciences, University of Macau, Macau SAR 999078, China, and.
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.affiliation: the Department of Developmental Biology, University of Texas Southwestern, Dallas, Texas 75390.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Graff
authors.affiliation: From the Centre for Research in Reproduction and Development, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada, daniel.bernard@mcgill.ca.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
mesh_terms: D000818:Animals; D005091:Exons; D005260:Female; D005640:Follicle Stimulating Hormone / Q000096:biosynthesis*; D052681:Gonadotrophs / Q000378:metabolism*; D007247:Infertility, Female / Q000235:genetics; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051900:Smad3 Protein / Q000235:genetics / Q000502:physiology*; D051901:Smad4 Protein / Q000235:genetics / Q000502:physiology; D013091:Spermatogenesis / Q000235:genetics
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D005640:Follicle Stimulating Hormone
keywords: SMAD transcription factor; activin; follicle-stimulating hormone (FSH); gene knock-out; pituitary gland