Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome

Jennifer J. Hofmann, Anais Briot, Josephine Enciso, Ann C. Zovein, Shuxun Ren, Zhen W. Zhang, Freddy Radtke, Michael Simons, Yibin Wang, M. Luisa Iruela-Arispe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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 endothelialspecific 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.

Original languageEnglish (US)
Pages (from-to)4449-4460
Number of pages12
JournalDevelopment (Cambridge)
Issue number23
StatePublished - Dec 1 2012


  • Aortic valves
  • Cardiac valves
  • EndMT
  • Mouse
  • Notch

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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