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Regulation of Fgf10 Gene Expression in the Prostate: Identification of Transforming Growth Factor-ß1 and Promoter Elements

Medical Research Council Human Reproductive Sciences Unit (D.C.T., A.A.T.), Centre for Reproductive Biology, The University of Edinburgh, Edinburgh EH16 4SB, Scotland, United Kingdom; and Division of Pediatric Cardiology (J.C.G.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Axel A. Thomson, Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The University of Edinburgh Chancellor’s Building, 49 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SB, Scotland, United Kingdom. E-mail: axel.thomson{at}hrsu.mrc.ac.uk.

Fibroblast growth factor 10 (FGF10) is a mesenchymal paracrine-acting factor that plays a key role in the organogenesis of the prostate, and Fgf10 transcripts exhibit a highly restricted expression pattern within prostatic mesenchyme. To study the regulation of Fgf10 we have used organ rudiments grown in vitro as well as a primary stromal cell system derived from the ventral mesenchymal pad (VMP), a condensed area of mesenchyme known to induce prostatic organogenesis. Characterization of VMP cells (VMPCs) showed that they retained expression of AR as well as transcripts for FGF10 and TGFß1, -2, and -3. We propose that VMPCs are a good model of specialized mesenchyme involved in prostatic organogenesis and are distinct from general urogenital sinus mesenchyme/stroma. Treatment of VMPCs with TGFß1 resulted in a rapid and transient decrease in Fgf10 transcript levels, which were reduced 9-fold at 3 h. TGFß1 also inhibited Fgf10 expression in VMP organ rudiments grown in vitro. To further analyze Fgf10 regulation, 6 kb of mouse genomic sequence 5' to the translation start site was characterized by promoter analysis. Deletion analysis of the Fgf10 promoter in VMPCs identified a region of the promoter that mediated a significant proportion of promoter activity as well as mediating promoter down-regulation by TGFß1. This element was located between nucleotides -182 and -172 and contained a consensus Sp1 binding site. Taken together, our data suggest that TGFß1 is a regulator of Fgf10 expression in prostatic mesenchyme and that a proximal element within the Fgf10 promoter plays an important role in its regulation and expression.

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