IFN-gamma overexpression within the pancreas is not sufficient to rescue Pax4, Pax6, and Pdx-1 mutant mice from death

In the presence of interferon-gamma (IFN-gamma), pancreatic ductal epitheli al cells grow continuously, and islets undergo neogenesis. To determine whe ther these new islets are derived from conventional precursors, we tested w hether IFN-gamma can complement the loss of transcription factors known to regulate pancreatic development. We analyzed the effect of a transgene on l ethality in mice lacking the transcription factors Pax4, Pax6, or Pdx-1, by intercrossing such mice with transgenic mice whose pancreatic cells make I FN-gamma (ins-IFN-gamma mice). However, IFN-gamma expression did not rescue these mice from the lethal mutations, because no homozygous knockout mice carrying the IFN-gamma transgene survived, despite the survival of all othe r hemizygous gene combinations. This outcome demonstrates that the pathway for IFN-gamma regeneration requires the participation of Pax4, Pax6, and Pd x-1. We conclude that the striking islet regeneration observed in the ins-I FN-gamma NOD strain is regulated by the same transcription factors that con trol initial pancreatic development.