title: PDX1 in ducts is not required for postnatal formation of β-cells but is necessary for their subsequent maturation.
abstract: Pancreatic duodenal homeobox-1 (Pdx1), a transcription factor required for pancreatic development and maintenance of β-cell function, was assessed for a possible role in postnatal β-cell formation from progenitors in the pancreatic ducts by selectively deleting Pdx1 from the ducts. Carbonic anhydrase II (CAII)(Cre);Pdx1(Fl) mice were euglycemic for the first 2 postnatal weeks but showed moderate hyperglycemia from 3 to 7 weeks of age. By 10 weeks, they had near-normal morning fed glucose levels but showed severely impaired glucose tolerance and insulin secretion. Yet the loss of Pdx1 did not result in decreased islet and β-cell mass at 4 and 10 weeks of age. Within the same pancreas, there was a mixed population of islets, with PDX1 and MAFA protein expression normal in some cells and severely diminished in others. Even at 10 weeks, islets expressed immaturity markers. Thus, we conclude that Pdx1 is not necessary for the postnatal formation of β-cells but is essential for their full maturation to glucose-responsive β-cells.
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lili
authors.initials: L
authors.lastname: Guo
authors.forename: Akari
authors.initials: A
authors.lastname: Inada
authors.forename: Cristina
authors.initials: C
authors.lastname: Aguayo-Mazzucato
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hollister-Lock
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujitani
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein