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Background  Activins stimulate the synthesis of follicle stimulating hormone (FSH) in pituitary gonadotropes, at least in part, by inducing transcription of its beta subunit ( Fshb ). Evidence from several laboratories studying transformed murine LbetaT2 gonadotropes indicates that activins signal through Smad-dependent and/or Smad-independent pathways, similar to those used by transforming growth factor beta-1 (TGFB1) in other cell types. Therefore, given common intracellular signaling mechanisms of these two ligands, we examined whether TGFBs can also induce transcription of  Fshb  in LbetaT2 cells as well as in purified primary murine gonadotropes.    Methods  Murine  Fshb  promoter-reporter (-1990/+1 m Fshb -luc) activity was measured in LbetaT2 cells treated with activin A or TGFB1, and in cells transfected with either activin or TGFB receptors. The ability of the ligands to stimulate phosphorylation of Smads 2 and 3 in LbetaT2 cells was measured by western blot analysis, and expression of TGFB type I and II receptors was assessed by reverse transcriptase polymerase chain reaction in both LbetaT2 cells and primary gonadotropes purified from male mice of different ages. Finally, regulation of endogenous murine  Fshb  mRNA levels by activin A and TGFB1 in purified gonadotropes and whole pituitary cultures was measured using quantitative RT-PCR.    Results  Activin A dose-dependently stimulated -1990/+1 m Fshb -luc activity in LbetaT2 cells, but TGFB1 had no effect at doses up to 5 nM. Similarly, activin A, but not TGFB1, stimulated Smad 2 and 3 phosphorylation in these cells. Constitutively active forms of the activin (Acvr1b-T206D) and TGFB (TGFBR1-T204D) type I receptors strongly stimulated -1990/+1 m Fshb -luc activity, showing that mechanisms down stream of Tgfbr1 seem to be intact in LbetaT2 cells. RT-PCR analysis of LbetaT2 cells and whole adult murine pituitaries indicated that both expressed  Tgfbr1  mRNA, but that  Tgfbr2  was not detected in LbetaT2 cells. When cells were transfected with a human TGFBR2 expression construct, TGFB1 acquired the ability to significantly stimulate -1990/+1 m Fshb -luc activity. In contrast to LbetaT2 cells, primary murine gonadotropes from young mice (8–10 weeks) contained low, but detectable levels of  Tgfbr2  mRNA and these levels increased in older mice (1 yr). A second surprise was the finding that treatment of purified primary gonadotropes with TGFB1 decreased murine  Fshb  mRNA expression by 95% whereas activin A stimulated expression by 31-fold.    Conclusion  These data indicate that TGFB1-insensitivity in LbetaT2 cells results from a deficiency in  Tgfbr2  expression. In primary gonadotropes, however, expression of  Tgfbr2  does occur, and its presence permits TGFB1 to inhibit  Fshb  transcription, whereas activin A stimulates it. These divergent actions of activin A and TGFB1 were unexpected and show that the two ligands may act through distinct pathways to cause opposing biological effects in primary murine gonadotropes.

Differential regulation of follicle stimulating hormone by activin A and TGFB1 in murine gonadotropes