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Dutta, S, Gannon, M, Peers, B, Wright, C, Bonner-Weir, S and Montminy, M (2001) PDX:PBX complexes are required for normal proliferation of pancreatic cells during development. Proc. Natl. Acad. Sci. U.S.A. 98:1065-70

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

PubMed PMC14709 Online version:10.1073/pnas.031561298

Animals; Animals, Newborn; Cell Division; DNA-Binding Proteins/physiology; Death; Glucose/metabolism; Homeodomain Proteins/genetics; Homeodomain Proteins/physiology; Homeostasis; Islets of Langerhans/cytology; Islets of Langerhans/growth & development; Islets of Langerhans/physiology; Mice; Mice, Knockout; Mice, Transgenic; Morphogenesis; Mutagenesis, Site-Directed; Pancreas/cytology; Pancreas/growth & development; Pancreas/physiology; Pancreatic Ducts/cytology; Pancreatic Ducts/growth & development; Pancreatic Ducts/physiology; Promoter Regions, Genetic; Proto-Oncogene Proteins/physiology; Rats; Trans-Activators/deficiency; Trans-Activators/genetics; Trans-Activators/physiology