Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation

The Notch gene family encodes large transmembrane receptors that are compon ents of an evolutionarily conserved intercellular signaling mechanism. To a ssess the in vivo role of the Notch2 gene, we constructed a targeted mutati on, Notch2(del1), Unexpectedly, we found that alternative splicing of the N otch2(del1) mutant allele leads to the production of two different in-frame transcripts that delete either one or two EGF repeats of the Notch2 protei n, suggesting that this allele is a hypomorphic Notch2 mutation. Mice homoz ygous for the Notch2(del1) mutation died perinatally from defects in glomer ular development in the kidney. Notch2(del1)/Notch2(del1) mutant kidneys we re hypoplastic and mutant glomeruli lacked a normal capillary tuft, The Not ch ligand encoded by the Jag1 gene was expressed in developing glomeruli in cells adjacent to Notch2-expressing cells, We show that mice heterozygous for both the Notch2(del1) and Jag1(dDSL) mutations exhibit a glomerular def ect similar to, but less severe than, that of Notch2(del1)/Notch2(del1) hom ozygotes. The co-localization and genetic interaction of Jag1 and Notch2 im ply that this ligand and receptor physically interact, forming part of the signal transduction pathway required for glomerular differentiation and pat terning, NotCh2(del1)/Notch2(del1) homozygotes also display myocardial hypo plasia, edema and hyperplasia of cells associated with the hyaloid vasculat ure of the eye, These data identify novel developmental roles for Notch2 in kidney, heart and eye development.