Research on pancreatic cell differentiation and morphogenesis was invigorated by the discovery that many pancreatic disorders arise from defects at different stages of development. The identification of the molecular mechanisms and genetic components that govern pancreas formation has thus turned into a major goal, because these findings should provide tools for better treatment and prevention of pancreatic diseases. Recent studies from my group identified the homeobox-containing gene Prox1 as a novel regulator of mouse pancreas development. Analysis of Prox1-nullizygous embryos suggests that Prox1 regulates pancreatic epithelial-cell proliferation, and that it plays an important role in controlling branching morphogenesis, the expansion of endocrine precursors, and differentiation of exocrine cells. Deciphering the molecular mechanisms whereby Prox1 controls these processes, all of which are absolutely required to form a normal pancreas, should provide us with a novel entry point in helping to understand different aspects of pancreatic organogenesis. The main purpose of this grant proposal is to precisely characterize the functional role of Prox1 in mouse embryonic pancreata by performing a detailed molecular analysis of the pathway(s) regulated by Prox1 in this tissue. To this end I propose the following specific aims: I. To precisely determine the functional role of Prox1 in pancreatic organogenesis, by:A: Revealing proliferation-specific alterations in pancreatic cells of Prox1-nullizygous embryos.B: Determining possible function(s) of Prox1 in pancreatic tissue at later developmental stages.C: Analyzing possible epistasis between Prox1 and Pdx1 in the control of pancreatic growth. II. To identify additional players (epithelial-derived and mesenchymal-derived) participating in thepathway normally regulated by Prox1 during pancreas development, by:A: Determining autonomous and/or non-cell autonomous effects of Prox1 in developing pancreata.B: Identifying soluble and membrane-bound factors participating in this pathway.C: Identifying genes acting downstream of Prox1 during pancreas development. With the proposed studies we expect not only to uncover the molecular pathway(s) regulated by Prox1 during mouse pancreas development, but also to further define important mechanisms involved in mammalian pancreas development and to identify novel genes involved in this process. Our long-term goal is to use this knowledge and the generated molecular markers and mouse mutants to enhance our understanding of pancreas development and pancreatic diseases.
