Sonic hedgehog induces prostate development by activating a cascade of developmental factors. This application will characterize and test a postulated mechanism for the induction of normal human prostate development. Benign enlargement of the prostate gland in aging men occurs by focal, progressive growth. It displays a variegated histology and complex architecture that mimics normal prostate morphogenesis. My study of fetal prostate development will provide novel insights into a possible mechanism for benign hyperplastic growth in the adult and suggest new approaches to prevent and arrest abnormal growth. The prostate is an exocrine gland composed of a complex ductal system enmeshed in a supporting stroma. During fetal prostate development the ductal system is formed by outgrowths of urogenital sinus epithelium (UGS) into a surrounding mesenchyme. Testosterone stimulates prostate development, but the molecular mechanisms which initiate ductal outgrowth remain unknown. A highly conserved mechanism of induction that operates in embryonic development of many different organ systems involves a developmental cascade induced by the product of the gene sonic hedgehog (Shh). The Shh catalyzes development by activating expression of several downstream genes which regulate cell proliferation, apoptosis, and morphogenesis. The Shh initiates and maintains expression of fibroblast growth factors; it induces TGF beta-related bone morphogenetic proteins; and it activates expression of specific Hox genes. I will present preliminary evidence that this highly conserved inductive mechanism also initiates prostate development: 1) the Shh is expressed in the UGS during the period of prostate induction and expression correlates with prostate ductal budding; 2) prostate development is blocked by the presence of Shh-antibody; and 3) three likely targets of Shh regulation, including keratinocyte growth factor (FGF-7), bone morphogenetic protein (BMP-4), and Hox-d13 are all expressed in the fetal prostate. I postulate that Shh induces prostate development by activating expression of FGF-7, BMP-4, and Hox-d13. I will use quantitative assays for gene expression and localization studies to correlate expression of Shh with regulation of expression of FGF-7, BMP-4, and Hox-d13 in the developing prostate. I will experimentally test the ability to induce prostate development and activate expression of FGF-7, BMP-4, and Hox-d13. Finally, I will examine the growth related effects of FGF-7 and BMP-4 in the developing prostate by quantitatively assaying the effect of locally applied FGF-7 and BMP-4 on epithelial and mesenchymal proliferation and apoptosis.
