title: Inhibition of Jagged-mediated Notch signaling disrupts zebrafish biliary development and generates multi-organ defects compatible with an Alagille syndrome phenocopy.
abstract: The Alagille Syndrome (AGS) is a heritable disorder affecting the liver and other organs. Causative dominant mutations in human Jagged 1 have been identified in most AGS patients. Related organ defects occur in mice that carry jagged 1 and notch 2 mutations. Multiple jagged and notch genes are expressed in the developing zebrafish liver. Compound jagged and notch gene knockdowns alter zebrafish biliary, kidney, pancreatic, cardiac and craniofacial development in a manner compatible with an AGS phenocopy. These data confirm an evolutionarily conserved role for Notch signaling in vertebrate liver development, and support the zebrafish as a model system for diseases of the human biliary system.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6058, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Lorent
authors.forename: Sang-Yeob
authors.initials: SY
authors.lastname: Yeo
authors.forename: Takaya
authors.initials: T
authors.lastname: Oda
authors.forename: Settara
authors.initials: S
authors.lastname: Chandrasekharappa
authors.forename: Ajay
authors.initials: A
authors.lastname: Chitnis
authors.forename: Randolph P
authors.initials: RP
authors.lastname: Matthews
authors.forename: Michael
authors.initials: M
authors.lastname: Pack
mesh_terms: D016738:Alagille Syndrome / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D001652:Bile Ducts / Q000196:embryology / Q000378:metabolism; D001659:Biliary Tract / Q000196:embryology* / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008024:Ligands; D008099:Liver / Q000033:anatomy & histology / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008322:Mammals / Q000033:anatomy & histology; D008565:Membrane Proteins / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D015027:Zebrafish / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C495207:Jag3 protein, zebrafish; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D029961:Zebrafish Proteins; C000606276:jag1a protein, zebrafish; C495205:jag2b protein, zebrafish