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

B McCright, X Gao, L Shen, J Lozier, Y Lan… - …, 2001 - journals.biologists.com
B McCright, X Gao, L Shen, J Lozier, Y Lan, M Maguire, D Herzlinger, G Weinmaster…
Development, 2001journals.biologists.com
The Notch gene family encodes large transmembrane receptors that are components of an
evolutionarily conserved intercellular signaling mechanism. To assess the in vivo role of the
Notch2 gene, we constructed a targeted mutation, Notch2 del1. Unexpectedly, we found that
alternative splicing of the Notch2 del1 mutant allele leads to the production of two different in-
frame transcripts that delete either one or two EGF repeats of the Notch2 protein, suggesting
that this allele is a hypomorphic Notch2 mutation. Mice homozygous for the Notch2 del1 …
Abstract
The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the in vivo role of the Notch2 gene, we constructed a targeted mutation, Notch2del1. Unexpectedly, we found that alternative splicing of the Notch2del1mutant allele leads to the production of two different in-frame transcripts that delete either one or two EGF repeats of the Notch2 protein, suggesting that this allele is a hypomorphic Notch2 mutation. Mice homozygous for the Notch2del1 mutation died perinatally from defects in glomerular development in the kidney. Notch2del1/Notch2del1 mutant kidneys were hypoplastic and mutant glomeruli lacked a normal capillary tuft. The Notch 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 Notch2del1 and Jag1dDSL mutations exhibit a glomerular defect similar to, but less severe than, that of Notch2del1/Notch2del1 homozygotes. The co-localization and genetic interaction of Jag1 and Notch2 imply that this ligand and receptor physically interact, forming part of the signal transduction pathway required for glomerular differentiation and patterning. Notch2del1/Notch2del1 homozygotes also display myocardial hypoplasia, edema and hyperplasia of cells associated with the hyaloid vasculature of the eye. These data identify novel developmental roles for Notch2 in kidney, heart and eye development.
journals.biologists.com