Improved glucose tolerance and acinar dysmorphogenesis by targeted expression of transcription factor PDX-1 to the exocrine pancreas

The homeodomain protein PDX-1 is critical for pancreas development and is a key regulator of insulin gene expression. PDX-1 nullizygosity and haploins ufficiency in mice and humans results in pancreatic agenesis and diabetes, respectively. At embryonic day (e) 10.5, PDX-1 is expressed in all pluripot ential gut-derived epithelial cells destined to differentiate into the exoc rine and endocrine pancreas. At e15, PDX-1 expression is downregulated in e xocrine cells, but remains high in endocrine cells. The aim of this study w as to determine whether targeted overexpression of PDX-1 to the exocrine co mpartment; of the developing pancreas at e15 would allow for respecificatio n of the exocrine cells. Transgenic (TG) mice were generated in which PDX-1 was expressed in the exocrine pancreas using the exocrine-specific elastas e-1 promoter. These mice exhibited a marked dysmorphogenesis of the exocrin e pancreas, manifested by increased rates of replication and apoptosis in a cinar cells and a progressive fatty infiltration of the exocrine pancreas w ith age. Interestingly, the TG mice exhibited improved glucose tolerance, b ut absolute beta -cell mass was not increased. These findings indicate that downregulation of PDX-1 is required for the proper maintenance of the exoc rine cell phenotype and that upregulation of PDX-1 in acinar cells affects beta -cell function. The mechanisms underlying these observations remain to be elucidated.