PDX : PBX complexes are required for normal proliferation of pancreatic cells during development

The homeobox factor PDX-1 is a key regulator of pancreatic morphogenesis an d glucose homeostasis; targeted disruption of the PDX-1 gene leads to pancr eatic agenesis in pdx-1(-/-) homozygotes. Pdx-1 heterozygotes develop norma lly, but they display glucose intolerance in adulthood. Like certain other homeobox proteins, PDX-1 contains a consensus FPWMK motif that promotes het erodimer formation with the ubiquitous homeodomain protein PBX. To evaluate the importance of PDX-1:PBX complexes in pancreatic morphogenesis and gluc ose homeostasis, we expressed either wild-type or PBX interaction defective PDX-1 transgenes under control of the PDX-1 promoter. Both wild-type and m utant PDX-1 transgenes corrected glucose intolerance in pdx-1 heterozygotes . The wild-type PDX-1 transgene rescued the development of all pancreatic l ineages in pdx-1(-/-) animals, and these mice survived to adulthood. In con trast, pancreata from pdx-1(-/-) mice expressing the mutant PDX-1 transgene were hypoplastic, and these mice died within 3 weeks of birth from pancrea tic insufficiency. All pancreatic cell types were observed in pdx-1(-/-) mi ce expressing the mutant PDX-1 transgene; but the islets were smaller, and increased numbers of islet hormone-positive cells were noted within the duc tal epithelium. These results indicate that PDX-1:PBX complexes are dispens able for glucose homeostasis and for differentiation of stem cells into duc tal, endocrine, and acinar lineages; but they are essential for expansion o f these populations during development.