title: β-catenin stabilization in gonadotropes impairs FSH synthesis in male mice in vivo.
abstract: Although classically considered a WNT signaling intermediary, β-catenin (CTNNB1) can also mediate GnRH induction of gonadotropin β-subunit (Fshb and Lhb) transcription in the murine gonadotrope-like cell line LβT2. Here, we assessed CTNNB1's role in gonadotropin synthesis in vivo. We used a Cre/lox approach to introduce both gain- and loss-of-function mutations in the murine Ctnnb1 gene in gonadotrope cells. Gonadotropin production and fertility were normal in Ctnnb1 knockout mice. Similarly, females harboring a deletion of exon 3 of Ctnnb1, which stabilizes the resulting CTNNB1 protein, showed normal fertility and gonadotropin synthesis. Interestingly, males with the activating CTNNB1-Δexon 3 mutation exhibited 50% reductions in FSH synthesis and secretion, without a corresponding change in LH. This selective regulation of FSH suggested an alteration in the activin/inhibin/follistatin system. Indeed, CTNNB1-Δexon 3 males showed a 60% increase in serum inhibin B levels, and in culture, their pituitaries exhibited a greater sensitivity to exogenous inhibin than controls. At the same time, pituitary, but not testicular, follistatin (Fst) expression was increased significantly in these mice. Castration normalized FSH levels in CTNNB1-Δexon 3 males to those seen in castrated controls. Paradoxically, pituitaries from CTNNB1-Δexon 3 males exhibited greater basal and activin-stimulated FSH synthesis in vitro. Similarly, CTNNB1-Δexon 3 overexpression potentiated activin A-induced murine Fshb promoter activity in LβT2 cells. Together, these results indicate that CTNNB1 is dispensable for gonadotropin synthesis in vivo. However, sustained CTNNB1 signaling potentiates activin-induced Fshb expression in gonadotropes, but this effect is overcome in vivo by enhanced inhibin feedback sensitivity and Fst expression.
authors.affiliation: Departments of Pharmacology and Therapeutics (V.K., Y.W., X.Z., S.K., D.J.B.) and Animal Science (R.L., S.K.), McGill University, Montréal, Canada H3G 1Y6; Département de Biomédecine Vétérinaire (D.B., V.K., A.B., C.R., C.C.) and Département de Pathologie et Microbiologie (M.P.), Université de Montréal, St-Hyacinthe, Canada J2S 7C6; and Department of Pharmacology and Toxicology (U.B.), University of Saarland School of Medicine, 66421 Homburg, Germany.
authors.forename: Derek
authors.initials: D
authors.lastname: Boerboom
authors.forename: Vikas
authors.initials: V
authors.lastname: Kumar
authors.forename: Alexandre
authors.initials: A
authors.lastname: Boyer
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Romain
authors.initials: R
authors.lastname: Lambrot
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.forename: Charlène
authors.initials: C
authors.lastname: Rico
authors.forename: Ulrich
authors.initials: U
authors.lastname: Boehm
authors.forename: Marilène
authors.initials: M
authors.lastname: Paquet
authors.forename: Christophe
authors.initials: C
authors.lastname: Céleste
authors.forename: Sarah
authors.initials: S
authors.lastname: Kimmins
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D005298:Fertility; D005640:Follicle Stimulating Hormone / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D008297:Male; D051379:Mice; D009919:Orchiectomy; D012671:Seminiferous Tubules; D013094:Spermatozoa; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D051176:beta Catenin; D005640:Follicle Stimulating Hormone