I will study a molecular mechanism which regulates growth in the developing prostate ducts and determines how manipulations that increase or decrease the activity of this mechanism alter prostate development and influence the extent of growth. This study will provide new insights into potential mechanisms for abnormal growth, provide an animal model for BPH, and suggest new pharmacologic approaches to control prostate growth. Prostate development begins when urogenital sinus epithelium grows into the surrounding mesenchyme and initiates a sustained process of ductal growth and branching. Testosterone is a stimulus to ductal development. However, growth normally stops at a defined endpoint despite the continued presence of testosterone - indicating that other factors regulate the extent of growth. In several well-studied systems the Hox genes are dominant regulators of growth in development. Hox genes function as transcriptional regulators. Each Hox gene is expressed in a time and region specific manner and exerts a permissive overarching influence on cell proliferation and growth. The Hox genes are called the morphogenetic clock since time-dependent down-regulation arrests morphogenesis and caps the potential for further growth. I have found that the gene Hox-d13 is expressed in the ducts of the developing prostate. Expression down- regulates as morphogenesis is completed. Retinoic acid, a direct regulator of the Hox genes, inhibits Hox-d13 expression in the developing prostate. Ductal morphogenesis is inhibited and a stunted adult prostate ductal system results. I postulate that Hox-d13 expression regulates the extent of prostate ductal growth. I will use a quantitative assay for Hox-d13 expression, localization studies, and quantitative analysis of prostate ductal morphogenesis to examine the correlation of Hox-d13 expression with ductal growth in normal development. I will then determine the effect on prostate development of reversible inhibition of Hox-d13 expression by retinoic acid, loss of expression in (an existing) transgenic Hox-d13 """"""""knockout"""""""" mouse, and overexpression in a proposed transgenic animal.
