Embryonic lethality and vascular defects in mice lacking the Notch ligand JAGGED1

The Notch signaling pathway is an evolutionarily conserved intercellular si gnaling mechanism essential for embryonic development in mammals. Mutations in the human JAGGED1 (JAG1) gene, which encodes a ligand for the Notch fam ily of transmembrane receptors, cause the autosomal dominant disorder Alagi lle syndrome. We have examined the in vivo role of the mouse Jag1 gene by c reating a null allele through gene targeting. Mice homozygous for the Jag1 mutation die from hemorrhage early during embryogenesis, exhibiting defects in remodeling of the embryonic and yolk sac vasculature. We mapped the Jag 1 gene to mouse chromosome 2, in the vicinity of the Coloboma (Cm) deletion , Molecular and complementation analyses revealed that the Jag1 gene is fun ctionally deleted in the Cm mutant allele, Mice heterozygous for the Jag1 n ull allele exhibit an eye dysmorphology similar to that of Cm/+ heterozygot es, but do not exhibit other phenotypes characteristic of Cm/+ mice or of h umans with Alagille syndrome, These results establish the phenotype of Cm/ mice as a contiguous gene deletion syndrome and demonstrate that Jag1 is e ssential for remodeling of the embryonic vasculature.