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 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.
Krakowski
M
M
The Scripps Research Institute, Department of Immunology, La Jolla, California 92037, USA.
Yeung
B
B
Abdelmalik
R
R
Good
A
A
Mocnik
L
L
Sosa-Pineda
B
B
St-Onge
L
L
Gruss
P
P
Sarvetnick
N
N
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000209:etiology; D005136:Eye Proteins; D005260:Female; D005934:Glucagon / Q000096:biosynthesis; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D007515:Islets of Langerhans / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012038:Regeneration; D012097:Repressor Proteins; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D007371:Interferon-gamma; D005934:Glucagon