DEFECTS IN LIMB, CRANIOFACIAL, AND THYMIC DEVELOPMENT IN JAGGED2 MUTANT MICE

The Notch signaling pathway is a conserved intercellular signaling mec hanism that is essential for proper embryonic development in numerous metazoan organisms. We have examined the in vivo role of the Jagged2 ( Jag2) gene, which encodes a ligand for the Notch family of transmembra ne receptors, by making a targeted mutation that removes a domain of t he Jagged2 protein required for receptor interaction. Mice homozygous for this deletion die perinatally because of defects in craniofacial m orphogenesis. The mutant homozygotes exhibit cleft palate and fusion o f the tongue with the palatal shelves. The mutant mice also exhibit sy ndactyly (digit fusions) of the fore-and hindlimbs. The apical ectoder mal ridge (AER) of the limb buds of the mutant homozygotes is hyperpla stic, and we observe an expanded domain of Fgf8 expression in the AER. In the foot plates of the mutant homozygotes, both Bmp2 and Bmp7 expr ession and apoptotic interdigital cell death are reduced. Mutant homoz ygotes also display defects in thymic development, exhibiting altered thymic morphology and impaired differentiation of gamma delta lineage T cells. These results demonstrate that Notch signaling mediated by Ja g2 plays an essential role during limb, craniofacial, and thymic devel opment in mice.