Abstract
The mechanisms that control the emergence of different anterior pituitary cells from a common stem cell population are largely unknown. The immortalized GHFT cells derived from targeted expression of SV40 T antigen to mouse pituitary display characteristics of somatolactotropic progenitors in that they express the transcription factor GHF-1 (Pit-1) but not growth hormone (GH) or prolactin (PRL). We searched for factors capable of inducing lactotropic 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. However, induction of PRL expression was incomplete in FGF-2-treated cells, suggesting that additional factors are necessary to attain high levels of PRL 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 factors 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. Moreover, FGF-2 effect on lactotrope differentiation is mediated, at least partially, by stimulation of the Ras-signaling pathway. Our results suggest that, indeed, GHFT cells represent a valid model for studying lactotropic differentiation and that FGF-2 could play a key role both in initiating lactotrope differentiation and maintaining PRL expression.
Highlights
That are highly specialized and synthesize distinct peptide hormones are sequentially derived from a common progenitor cell population within the anterior pituitary anlagen, Rathke’s pouch [1]
GHFT cells represent a valid model for studying lactotropic differentiation and that fibroblast growth factor-2 (FGF-2) could play a key role both in initiating lactotrope differentiation and maintaining PRL expression
Screening for Factors That Induce PRL Expression in GHFT Cells—To identify extracellular factors capable of inducing PRL expression in GHFT precursor cells, we tested several hormones, peptides, and growth factors known to have a stimulatory effect on synthesis and/or release of PRL in differentiated lactotropes
Summary
That are highly specialized and synthesize distinct peptide hormones are sequentially derived from a common progenitor cell population within the anterior pituitary anlagen, Rathke’s pouch [1]. Using the 5Ј GHF-1 regulatory region to target the immortalizing oncoprotein SV40 T-antigen in transgenic mice has immortalized this cell type Mice expressing this transgene exhibit dramatic dwarfism and develop pituitary tumors, which express high levels of GHF-1 transcripts, low levels of GHF-1 protein, and no GH or PRL [10]. Growth factors, and oncogenes act in conjunction with GHF-1 to regulate pituitary-specific expression of the PRL gene Those factors include ligands for nuclear hormone receptors [11, 12], hypophysiotropic peptides that activate the protein kinase A or protein kinase C pathways [13,14,15,16], or ligands of tyrosine kinase growth factor receptors [17,18,19,20]. Our results indicate that FGF-2 is a strong up-regulator of PRL gene expression in somatolactotropic progenitors and that this factor is a strong candidate for a physiological inducer of lactotropic differentiation in vivo and probably in maintaining the lactotropic phenotype of differentiated cells
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