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http://purl.uniprot.org/citations/25446530http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25446530http://www.w3.org/2000/01/rdf-schema#comment"

Unlabelled

Notch signaling plays an acknowledged role in bile-duct development, but its involvement in cholangiocyte-fate determination remains incompletely understood. We investigated the effects of early Notch2 deletion in Notch2(fl/fl)/Alfp-Cre(tg/-) ("Notch2-cKO") and Notch2(fl/fl)/Alfp-Cre(-/-) ("control") mice. Fetal and neonatal Notch2-cKO livers were devoid of cytokeratin19 (CK19)-, Dolichos-biflorus agglutinin (DBA)-, and SOX9-positive ductal structures, demonstrating absence of prenatal cholangiocyte differentiation. Despite extensive cholestatic hepatocyte necrosis and growth retardation, mortality was only ~15%. Unexpectedly, a slow process of secondary cholangiocyte differentiation and bile-duct formation was initiated around weaning that histologically resembled the ductular reaction. Newly formed ducts varied from rare and non-connected, to multiple, disorganized tubular structures that connected to the extrahepatic bile ducts. Jaundice had disappeared in ~30% of Notch2-cKO mice by 6 months. The absence of NOTCH2 protein in postnatally differentiating cholangiocyte nuclei of Notch2-cKO mice showed that these cells had not originated from non-recombined precursor cells. Notch2 and Hnf6 mRNA levels were permanently decreased in Notch2-cKO livers. Perinatally, Foxa1, Foxa2, Hhex, Hnf1β, Cebpα and Sox9 mRNA levels were all significantly lower in Notch2-cKO than control mice, but all except Foxa2 returned to normal or increased levels after weaning, coincident with the observed secondary bile-duct formation. Interestingly, Hhex and Sox9 mRNA levels remained elevated in icteric 6 months old Notch2-cKOs, but decreased to control levels in non-icteric Notch2-cKOs, implying a key role in secondary bile-duct formation.

Conclusion

Cholangiocyte differentiation becomes progressively less dependent on NOTCH2 signaling with age, suggesting that ductal-plate formation is dependent on NOTCH2, but subsequent cholangiocyte differentiation is not."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.org/dc/terms/identifier"doi:10.1016/j.ydbio.2014.10.002"xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"de Waart D.R."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"Weeda V.B."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"Lamers W.H."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"Lemaigre F."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"Hakvoort T.B."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"Labruyere W.T."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"Gaemers I.C."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"Aronson D.C."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"Falix F.A."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/author"Poncy A."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/date"2014"xsd:gYear
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/name"Dev Biol"xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/pages"201-213"xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/title"Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning."xsd:string
http://purl.uniprot.org/citations/25446530http://purl.uniprot.org/core/volume"396"xsd:string
http://purl.uniprot.org/citations/25446530http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/25446530
http://purl.uniprot.org/citations/25446530http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/25446530
http://purl.uniprot.org/uniprot/P05201#attribution-7EA5D3290797641C090DBB38B2B09DC7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/25446530
http://purl.uniprot.org/uniprot/O35423#attribution-7EA5D3290797641C090DBB38B2B09DC7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/25446530
http://purl.uniprot.org/uniprot/P97429#attribution-7EA5D3290797641C090DBB38B2B09DC7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/25446530
http://purl.uniprot.org/uniprot/P53566#attribution-7EA5D3290797641C090DBB38B2B09DC7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/25446530
http://purl.uniprot.org/uniprot/P35582#attribution-7EA5D3290797641C090DBB38B2B09DC7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/25446530
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