Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.

The transcription factors pancreatic and duodenal homeobox 1 (Pdxl) and onecutl (Ocl) are coexpressed in muitipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and pdxl being maintained at high levels in beta-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the beta-cell maturity factor MafA. We therefore hypothesized that pdxl and Ocl cooperativity in MFCs impacts postnatal beta-cell maturation and function. Here our model of Pdxl-Ocl double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal beta-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14. we observed alterations in pancreatic insulin content in both pdxl heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2. Pcskl/2. AbccS) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous beta-cells would have an impaired ability to respond to stress. Indeed, we observed that beta-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.