The Role of Hox11 Paralogous Genes in Prostate Development

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DESCRIPTION (provided by applicant): Targeted gene disruption studies have confirmed that Hox genes affect prostate development, but phenotypes of single mutant animals have been generally mild, pleiotropic, and incompletely penetrant. Because of the nature of these defects, it has been difficult to determine the genetic function of Hox genes in the developing prostate. By removing all six functional copies of the Hox11 paralogous genes, we have generated animals with profound defects in the developing prostate. Preliminary data suggests that triple mutant animals display a very disrupted bud pattern and, while the anterior and dorsolateral lobes of the prostate bud from E18.5 urogenital sinuses, they do not branch or develop past this stage. Surviving four-allele animals show incomplete penetrance of these defects as adults. Together with previous data on single mutants in the Hox10 and Hox13 paralogous groups, it appears that the prostate develops in response to anteroposterior patterning signals from the AbdB Hox genes, with Hox10 genes patterning the anterior prostate, Hox11 genes patterning primarily the dorsolateral prostate and Hox13 genes patterning primarily the ventral prostate. The nature of these defects have important implications for understanding the development of this organ system, as well as beginning to understand potential roles for Hox genes have in disease. Results in the laboratory suggest that Hox11 proteins, together with Pax2 and Eya1, form a regulatory complex that, together can activate downstream genes, such as Six2 and Gdnf in the kidney. Both of these genes are also expressed in the developing prostate, and our preliminary data shows Gdnf functions in the developing prostate, supporting the conservation of this pathway in prostate development. We have also engineered new constructs in the Hox11 paralogous genes that produce null alleles, but also express fluorescently fusion proteins from the endogenous loci. Additionally, as triple mutant and high-allele mutants in the Hox11 colony die at newborn stages due to insufficient kidney development, we have worked out culture conditions that allow us to continue prostatic growth through early ductal morphogenesis. Using our newly generated fluorecent alleles in culture experiments will allow real-time imaging of Hox expression during early prostate organogenesis. We hypothesize that Hox11 paralogous genes contribute to patterning the dorsolateral prostate and their mesenchymal expression is necessary for branching morphogenesis and growth of this region of the developing prostate. These studies will provide key insights into the genetic and molecular basis of Hox regulation in prostate development.