"Diabetes is a degenerative disease affecting millions of persons worldwide. A cure for diabetes depends on replacing the insulin-producing ²-cells in the pancreas that are destroyed by the disease. An attractive strategy to attain this goal is to convert liver adult cells of the same patient into pancreatic ²-cells. The liver and pancreas share many aspects of their early development and are specified in adjacent regions of the endoderm, possibly from a common bipotent progenitor cell. Therefore, conversion of liver to pancreas is conceivable and should imply only few steps backward to a common progenitor and little epigenetic changes. However, how pancreatic versus hepatic fate decision occurs during development is still poorly understood. The aim of this proposal is two fold: to perform lineage analysis, and to study developmental regulators of pancreatic versus hepatic fate decision. We will use new genetic tools, based on the GFP and photoconvertible Kaede fluorescent proteins, to address: i. if the liver and pancreas arise from a common bipotent progenitor cell; ii. to trace in vivo; and iii. molecularly profile the presumptive precursor cell and its descendants in the mouse embryo. Our previous studies have identified target genes of the GATA factors that might act as intrinsic developmental regulators of the pancreatic versus hepatic fate decision. Both intrinsic factors together with extrinsic regulators, such as BMP, will be studied. We will test their potential to promote lineage reprogramming of liver to pancreas using the mouse as well as mouse embryonic stem cells as model systems. Understanding how distinct cell types arise from common multipotent progenitor cells is a major quest in developmental biology. Our findings will elucidate the spatiotemporal mechanisms that control pancreas versus liver fate decision. In addition, they will provide the blueprint for lineage reprogramming of adult hepatic cells to pancreas in diabetes cell-therapy."