INSULIN-PROMOTER-FACTOR-1 IS REQUIRED FOR PANCREAS DEVELOPMENT IN MICE

THE mammalian pancreas is a mixed exocrine and endocrine gland that, i n most species, arises from ventral and dorsal buds which subsequently merge to form the pancreas. In both mouse and rat the first histologi cal sign of morphogenesis of the dorsal pancreas is a dorsal evaginati on of the duodenum ai the level of the liver at around the 22-25-somit e stage, and shortly thereafter a ventral evagination appears as a der ivative of the liver diverticulum(1-3). Low levels of insulin gene tra nscripts are already present and restricted to the dorsal foregut endo derm at 20 somites, suggesting that pancreas- or insulin gene-specific transcriptional factors are present in this region before the onset o f morphogenesis(4). Insulin-promoter-factor 1 (IPF1) is a homeodomain protein which, in the adult mouse pancreas, is selectively expressed i n the beta-cells and binds to and transactivates the insulin promoter( 5). In mouse embryos, IPF1 expression is restricted to the developing pancreatic anlagen and is initiated when the foregut endoderm is commi tted to a pancreatic fate(5). We now show that mice homozygous for a t argeted mutation in the Ipf1 gene selectively lack a pancreas. The mut ant pups survive fetal development but die within a few days after bir th. The gastrointestinal part and all other internal organs were norma l in appearance. No pancreatic tissue and no ectopic expression of ins ulin or pancreatic amylase could be detected in mutant embryos and neo nates. These findings show that IPF1 is needed for the formation of th e pancreas and suggest that it acts to determine the fate of common pa ncreatic precursor cells and/or to regulate their propagation.