title: Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome.
abstract: The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis.
authors.affiliation: Molecular Biology Institute, University of California, Los Angeles, CA 90095,  USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hofmann
authors.forename: Anais
authors.initials: A
authors.lastname: Briot
authors.forename: Josephine
authors.initials: J
authors.lastname: Enciso
authors.forename: Ann C
authors.initials: AC
authors.lastname: Zovein
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.forename: Zhen W
authors.initials: ZW
authors.lastname: Zhang
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
mesh_terms: D016738:Alagille Syndrome / Q000235:genetics*; D000818:Animals; D002114:Calcinosis / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism; D003330:Coronary Vessel Anomalies / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism; D006345:Heart Septal Defects, Ventricular / Q000235:genetics / Q000378:metabolism; D006349:Heart Valve Diseases / Q000235:genetics* / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D009924:Organ Culture Techniques; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins