| First Author | Boerboom D | Year | 2015 |
| Journal | Endocrinology | Volume | 156 |
| Issue | 1 | Pages | 323-33 |
| PubMed ID | 25343272 | Mgi Jnum | J:215012 |
| Mgi Id | MGI:5604424 | Doi | 10.1210/en.2014-1296 |
| Citation | Boerboom D, et al. (2014) beta-catenin stabilization in gonadotropes impairs follicle-stimulating hormone synthesis in male mice in vivo. Endocrinology :en20141296 |
| abstractText | Though classically considered a WNT signaling intermediary, CTNNB1 (beta-catenin) can also mediate GnRH induction of gonadotropin beta subunit (Fshb and Lhb) transcription in the murine gonadotrope-like cell line LbetaT2. 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-Deltaexon 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-Deltaexon 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-Deltaexon 3 males to those seen in castrated controls. Paradoxically, pituitaries from CTNNB1-Deltaexon 3 males exhibited greater basal and activin-stimulated FSH synthesis in vitro. Similarly, CTNNB1-Deltaexon 3 overexpression potentiated activin A-induced murine Fshb promoter activity in LbetaT2 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. |
