Ectopically expressed PDX-1 in liver initiates endocrine and exocrine pancreas differentiation but causes dysmorphogenesis.
To date, the potency of pancreatic and duodenal homeobox gene 1 (PDX-1) in inducing differentiation into insulin-producing cells has been demonstrated in some cells and tissues. In order to carry out efficient screening of somatic tissues and cells that can transdifferentiate into beta-cell-like cells in response to PDX-1, we generated CAG-CAT-PDX1 transgenic mice carrying a transgene cassette composed of the chicken beta-actin gene (CAG) promoter and a floxed stuffer DNA sequence (CAT) linked to PDX-1 cDNA. When the mice were crossed with Alb-Cre mice, which express the Cre recombinase driven by the rat albumin gene promoter, PDX-1 was expressed in more than 50% of hepatocytes and cholangiocytes. The PDX-1 (+) livers expressed a variety of endocrine hormone genes such as insulin, glucagon, somatostatin, and pancreatic polypeptide. In addition, they expressed exocrine genes such as elastase-1 and chymotrypsinogen 1B. However, the mice exhibited marked jaundice due to conjugated hyperbilirubinemia, and the liver tissue displayed abnormal lobe structures and multiple cystic lesions. Thus, the in vivo ectopic expression of PDX-1 in albumin-producing cells was able to initiate but not complete the differentiation of liver cells into pancreatic cells. The conditional PDX-1 transgenic mouse system developed in this study appeared to be useful for efficient screening of PDX-1 responsive somatic tissues and cells.
Miyatsuka
T
T
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Kaneto
H
H
Kajimoto
Y
Y
Hirota
S
S
Arakawa
Y
Y
Fujitani
Y
Y
Umayahara
Y
Y
Watada
H
H
Yamasaki
Y
Y
Magnuson
M A
MA
Miyazaki
J
J
Hori
M
M
D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D002454:Cell Differentiation; D002455:Cell Division; D002645:Chickens; D004703:Endocrine System / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D018398:Homeodomain Proteins; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D010179:Pancreas / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution; D015534:Trans-Activators / Q000096:biosynthesis* / Q000502:physiology*; D019076:Transgenes; D014764:Viral Proteins / Q000378:metabolism
D018398:Homeodomain Proteins; D007328:Insulin; D010455:Peptides; D015534:Trans-Activators; D014764:Viral Proteins; C084010:pancreatic and duodenal homeobox 1 protein; D012313:RNA; C045073:Cre recombinase; D019426:Integrases