Ductal malformation and pancreatitis in mice caused by conditional Jag1 deletion.
OBJECTIVE
Alagille syndrome is an autosomal dominant disorder caused by mutations in Notch signaling pathway genes, usually JAGGED1. Up to 40% of Alagille syndrome patients also display exocrine pancreatic insufficiency, the pathobiology of which is unknown. Additionally, no mouse model recapitulating this aspect of the disease has been reported.


METHODS
We conditionally deleted both alleles of Jagged1 in the murine pancreas using Cre-loxP technology and analyzed histologic and morphologic features in postnatal and adult pancreas such as duct structure, acinar mass, and T-lymphocyte infiltration, as well as markers of pancreatic function, including fecal fat.


RESULTS
Jagged1-deficient mice displayed malformed pancreatic ducts with resulting acinar cell death, fatty infiltration of the parenchyma, fibrosis, pancreatitis, and pancreatic insufficiency.


CONCLUSIONS
Pancreatic ductal malformation and acinar cell loss may be responsible for pancreatic insufficiency in Jagged1-deficient mice and, by corollary, in Alagille syndrome patients.
Golson
Maria L
ML
Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Loomes
Kathleen M
KM
Oakey
Rebecca
R
Kaestner
Klaus H
KH
D017667:Adipocytes / Q000473:pathology; D016738:Alagille Syndrome / Q000235:genetics; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010183:Pancreatic Ducts / Q000002:abnormalities* / Q000473:pathology; D010195:Pancreatitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000072099:Serrate-Jagged Proteins
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D005947:Glucose