IFN-?? Overexpression Within the Pancreas Is Not Sufficient to Rescue Pax4, Pax6, and Pdx-1 Mutant Mice from Death

Abstract

In the presence of interferon-gamma (IFN-gamma), pancreatic ductal epithelial cells grow continuously, and islets undergo neogenesis. To determine whether these new islets are derived from conventional precursors, we tested whether IFN-gamma can complement the loss of transcription factors known to regulate pancreatic development. We analyzed the effect of a transgene on lethality in mice lacking the transcription factors Pax4, Pax6, or Pdx-1, by intercrossing such mice with transgenic mice whose pancreatic cells make IFN-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 other hemizygous gene combinations. This outcome demonstrates that the pathway for IFN-gamma regeneration requires the participation of Pax4, Pax6, and Pdx-1. We conclude that the striking islet regeneration observed in the ins-IFN-gamma NOD strain is regulated by the same transcription factors that control initial pancreatic development.

Development of cell markers for the identification and expansion of islet progenitor cells

“…This outcome demonstrates that the pathway for IFN‐γ‐regeneration requires the participation of Pax 4, Pax 6 and PDX‐1; IFN‐γ expression does not activate a novel pathway independent of these transcription factors. Rather, we believe that the striking islet regeneration observed in IFN‐γ transgenic mice is regulated by the same transcription factors that control initial pancreatic development 45. Indeed, PDX‐1 that is expressed only in the islets in the adult is induced in the ductal epithelial cells in some regeneration models 44, 46–48, and the expression of early endocrine precursors such as neuropeptide Y and tyrosine hydroxylase is also found in the IFN‐γ regenerating ductal epithelium, which further suggests that regeneration models are quite similar and recapitulate islet ontogeny observed during embryogenesis 49.…”