Molecular mechanisms regulating developmental maturation of pancreatic ductal cells

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Functional organs are created by arranging cells with different function into 3D structures allowing the organ to efficiently carry out its role in the body. In some organs, the creation of distinct specialized cell types occurs at the same time that the overall structure of the organ is created during embryonic development. Despite recent progress in elucidating the molecular mechanisms regulating cellular differentiation or establishing organ structure, a complete understanding of each of these processes and the links between the two remains a distant goal. In organs, such as the lung and pancreas, a highly branched tree structure serves to increase the surface area and number of functional units that can be packed into a small area. In addition, the branched tree serves as a conduit to deliver cellular products from the periphery of the organ to their destination. Thus, the function and structure of the branched network is critical for the function of the overall organ. The branching network in the pancreas is comprised of ductal cells. To date, we know very little about the gene programs regulating the growth and differentiation of this cell population during development. We recently developed genetic tools to specifically isolate or manipulate pancreatic ductal cells during their development. With these tools, we identified candidate genes potentially important for the differentiation of embryonic progenitor cells into mature, functioning pancreatic ducts. In this proposal, we will utilize these candidate genes to examine when ductal cells are specified during development. In addition, we will use the powerful genetic tools I developed to directly test whether these candidate genes are important for ductal cell differentiation or maturation. In sum, the proposed research program will provide new insight into the links between cellular differentiation and the establishment of organ structure and function.