Differentiation of lactotrope precursor GHFT cells in response to fibroblast growth factor-2

The mechanisms that control the emergence of different anterior pituitary c ells from a common stem cell population are largely unknown. The immortaliz ed GHFT cells derived from targeted expression of SV40 T antigen to mouse p ituitary display characteristics of somatolactotropic progenitors in that t hey express the transcription factor GHF-1 (Pit-1) but not growth hormone ( GH) or prolactin (PRL), We searched for factors capable of inducing lactotr opic differentiation of GHFT cells. PRL gene expression was not observed in cells subjected to a variety of stimuli, which induce PRL gene expression in mature lactotropes, Only fibroblast growth factor-2 (FGF-2) was able to initiate the transcription, synthesis, and release of PRL in GHFT cells. Ho wever, induction of PRL expression was incomplete in FGF-2-treated cells, s uggesting that additional factors are necessary to attain high levels of PR L transcription in fully differentiated lactotropes. We also show that the FGF-2 response element is located in the proximal PRL promoter. Stimulation of PRL expression by FGF-2 requires endogenous Ets factors and these facto rs as well as GHF-1 are expressed at low levels in the committed precursor, suggesting that these low levels are limiting for full PRL expression. Mor eover, FGF-P effect on lactotrope differentiation is mediated, at least par tially, by stimulation of the Has-signaling pathway. Our results suggest th at, indeed, GHFT cells represent a valid model for studying lactotropic dif ferentiation and that FGF-2 could play a key role both in initiating lactot rope differentiation and maintaining PRL expression.