Improved glucose tolerance and acinar dysmorphogenesis by targeted expression of transcription factor PDX-1 to the exocrine pancreas.
The homeodomain protein PDX-1 is critical for pancreas development and is a key regulator of insulin gene expression. PDX-1 nullizygosity and haploinsufficiency in mice and humans results in pancreatic agenesis and diabetes, respectively. At embryonic day (e) 10.5, PDX-1 is expressed in all pluripotential gut-derived epithelial cells destined to differentiate into the exocrine and endocrine pancreas. At e15, PDX-1 expression is downregulated in exocrine cells, but remains high in endocrine cells. The aim of this study was to determine whether targeted overexpression of PDX-1 to the exocrine compartment of the developing pancreas at e15 would allow for respecification of the exocrine cells. Transgenic (TG) mice were generated in which PDX-1 was expressed in the exocrine pancreas using the exocrine-specific elastase-1 promoter. These mice exhibited a marked dysmorphogenesis of the exocrine pancreas, manifested by increased rates of replication and apoptosis in acinar cells and a progressive fatty infiltration of the exocrine pancreas with age. Interestingly, the TG mice exhibited improved glucose tolerance, but absolute beta-cell mass was not increased. These findings indicate that downregulation of PDX-1 is required for the proper maintenance of the exocrine cell phenotype and that upregulation of PDX-1 in acinar cells affects beta-cell function. The mechanisms underlying these observations remain to be elucidated.
Heller
R S
RS
Department of Developmental Biology, Hagedorn Research Institute, DK 2820, Gentofte, Denmark. shll@hagedorn.dk
Stoffers
D A
DA
Bock
T
T
Svenstrup
K
K
Jensen
J
J
Horn
T
T
Miller
C P
CP
Habener
J F
JF
Madsen
O D
OD
Serup
P
P
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000502:physiology*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D010179:Pancreas / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D015854:Up-Regulation
D001786:Blood Glucose; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D010196:Pancreatic Elastase