title: Normal gonadotropin production and fertility in gonadotrope-specific Bmpr1a knockout mice.
abstract: Pituitary follicle-stimulating hormone (FSH) synthesis is regulated by transforming growth factorβsuperfamily ligands, most notably the activins and inhibins. Bone morphogenetic proteins (BMPs) also regulate FSHβ subunit (Fshb) expression in immortalized murine gonadotrope-like LβT2 cells and in primary murine or ovine primary pituitary cultures. BMP2 signals preferentially via the BMP type I receptor, BMPR1A, to stimulate murine Fshb transcription in vitro Here, we used a Cre-lox approach to assess BMPR1A's role in FSH synthesis in mice in vivo Gonadotrope-specific Bmpr1a knockout animals developed normally and had reproductive organ weights comparable with those of controls. Knockouts were fertile, with normal serum gonadotropins and pituitary gonadotropin subunit mRNA expression. Cre-mediated recombination of the floxed Bmpr1a allele was efficient and specific, as indicated by PCR analysis of diverse tissues and isolated gonadotrope cells. Furthermore, BMP2 stimulation of inhibitor of DNA binding 3 expression was impaired in gonadotropes isolated from Bmpr1a knockout mice, confirming the loss of functional receptor protein in these cells. Treatment of purified gonadotropes with small-molecule inhibitors of BMPR1A (and the related receptors BMPR1B and ACVR1) suppressed Fshb mRNA expression, suggesting that an autocrine BMP-like molecule might regulate FSH synthesis. However, deletion of Bmpr1a and Acvr1 in cultured pituitary cells did not alter Fshb expression, indicating that the inhibitors had off-target effects. In sum, BMPs or related ligands acting via BMPR1A or ACVR1 are unlikely to play direct physiological roles in FSH synthesis by murine gonadotrope cells.
authors.affiliation: Department of Pharmacology and TherapeuticsMcGill University, Montreal, Québec, Canada Centre for Research in Reproduction and DevelopmentMcGill University, Montreal, Québec, Canada.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and TherapeuticsMcGill University, Montreal, Québec, Canada Centre for Research in Reproduction and DevelopmentMcGill University, Montreal, Québec, Canada.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and TherapeuticsMcGill University, Montreal, Québec, Canada Centre for Research in Reproduction and DevelopmentMcGill University, Montreal, Québec, Canada.
authors.forename: Luisina
authors.initials: L
authors.lastname: Ongaro
authors.affiliation: Department of Pharmacology and ToxicologyUniversity of Saarland School of Medicine, Homburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Boehm
authors.affiliation: Department of Biologic and Materials SciencesSchool of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.affiliation: Department of Biologic and Materials SciencesSchool of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Pharmacology and TherapeuticsMcGill University, Montreal, Québec, Canada Centre for Research in Reproduction and DevelopmentMcGill University, Montreal, Québec, Canada daniel.bernard@mcgill.ca.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
mesh_terms: D030201:Activin Receptors, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005298:Fertility / Q000502:physiology*; D037201:Follicle Stimulating Hormone, beta Subunit / Q000096:biosynthesis / Q000235:genetics; D052681:Gonadotrophs / Q000187:drug effects / Q000502:physiology*; D006065:Gonadotropins, Pituitary / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D037201:Follicle Stimulating Hormone, beta Subunit; D006065:Gonadotropins, Pituitary; D012333:RNA, Messenger; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: Cre-lox; FSH; activin receptor-like kinase; bone morphogenetic protein; pituitary