Background & Aims: 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.
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