To identify and analyze the signaling pathways utilized during prostate development, and how they may be perturbed during carcinogenesis, we have been investigating the formation of the prostate gland in the mouse. During late embryogenesis, the prostate is induced from the urogenital sinus epithelium by as yet unidentified signal(s) from surrounding mesenchymal tissue, resulting in formation of epithelial buds that develop into the prostatic lobes. In particular, we and others have shown that the earliest stages of prostate development are marked by expression of the homeobox gene Nkx3.1, which is essential for normal prostate ductal morphogenesis.

Previous studies have demonstrated that the Hedgehog (Hh) signaling pathway plays a critical role in the development and patterning of many endodermally-derived tissues. In collaboration with David Berman and Phil Beachy's laboratory (Johns Hopkins), we have investigated the role of Sonic hedgehog (Shh) in formation of the prostate gland by examining the urogenital phenotype of Shh mutant fetuses. Consistent with earlier work reporting an essential role for Shh in prostate induction, we have found that Shh mutant fetuses display abnormal urogenital development and fail to form prostate buds. Unexpectedly, however, we have discovered that this prostate defect could be rescued by three different methods: renal grafting, explant culture in the presence of androgens, and administration of dihydrotestosterone (DHT) to pregnant mice, indicating that the prostate defect in Shh mutants is due to insufficient levels of androgens. Furthermore, we have found that inhibition of Hh pathway signaling by treatment with cyclopamine does not block prostate formation in explant culture, but instead produces morphological defects consistent with a role for Hh signaling in ductal patterning. Taken together, our studies indicate that the initial organogenesis of the prostate proceeds independently of Shh, but that Shh or other Hh ligands may play a role in subsequent events that pattern the prostate.