Beta-Catenin Stabilization in Gonadotropes Impairs Follicle-Stimulating Hormone Synthesis in Male Mice in Vivo
Presentation Number: OR16-5
Date of Presentation: March 6th, 2015
Daniel J Bernard*1, Vikas Kumar2, Alexandre Boyer3, Ying Wang1, Romain Lambrot4, Xiang Zhou2, Charlene Rico3, Ulrich Boehm5, Marilene Paquet3, Christophe Celeste3, Sarah Kimmins6 and Derek T Boerboom7
1McGill University, Montreal, QC, Canada, 2McGill Univ., Montreal, QC, Canada, 3Université de Montréal, 4McGill Univ, QC, Canada, 5University of Saarland School of Medicine, Homburg, Germany, 6McGill Univ, Montreal, QC, Canada, 7University of Montreal, Saint-Hyacinthe, QC, Canada
Though classically considered a WNT signaling intermediary, CTNNB1 (β-catenin) can also mediate GnRH nduction 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.
Nothing to Disclose: DJB, VK, AB, YW, RL, XZ, CR, UB, MP, CC, SK, DTB