Benign prostatic hyperplasia (BPH) has been postulated to arise from reactivation of embryonic growth pathways. The major goal of our research is to identify the molecular mechanisms that initiate fetal prostate development and to understand how reactivation of these mechanisms in the adult might cause hyperplasia. The prostate is an accessory exocrine sex organ composed of a secretory ductal system enmeshed in a supporting stroma. During fetal development, buds of urogenital sinus (UGS) epithelium grow into the surrounding mesenchyme and form ducts that grow and branch to form a complex ductal system. We have identified two important regulators of ductal development that exert opposing effects on growth. The first is the gene sonic hedgehog (Shh). Shh expression is upregulated by testosterone and localizes to the epithelium of buds that form the main prostatic ducts and to the epithelium of the growing prostatic ducts. The Shh gene product is a secreted signaling peptide that activates target genes in the adjacent UGS mesenchyme. Shh stimulates epithelial proliferation, induces budding in the UGS and promotes ductal branching during postnatal prostate development. The second factor is the gene Bone morphogenetic protein 4 (Bmp4). Bmp4 is expressed in the UGS mesenchyme. Expression surrounds sites of ductal budding and ensheaths the developing prostate ducts. Bmp4 inhibits epithelial proliferation, restricts ductal budding and restrains ductal branching. Our studies reveal that Shh and Bmp4 are expressed in tightly coordinated, complementary patterns of expression that echo their opposing influences on ductal growth. We propose to evaluate the hypothesis that Shh and Bmp4 collaborate to control prostate ductal budding and branching. We expect to show that Shh and Bmp4 act as independent regulators that control ductal growth by exerting opposing effects on epithelial proliferation. We will characterize the effects of Shh and Bmp4 on ductal growth, link their expression to the influence of testosterone and a regulator of ductal budding (Hox-dIS), and characterize the effects of Shh overactivity and Bmp4 insufficiency on ductal budding and branching. We expect to provide new insights into the regulation of prostate growth that will have particular significance in light of our recent observation that Shh and Bmp4 are re-expressed in BPH.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-UROL (01))
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Wilder, Elizabeth L
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University of Wisconsin Madison
Schools of Medicine
United States
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