Notch signaling is essential for vascular morphogenesis in mice

TLDR

The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. The study generated Notch4-deficient mice to assess the role of Notch4. The authors created Notch4 knockout mice by gene targeting and examined ligand expression, finding that Dll4 is the sole ligand expressed in the early embryonic vasculature consistent with Notch1/Notch4 signaling. Notch4 alone is dispensable for embryonic development, but its genetic interaction with Notch1 and double mutants produce severe vascular remodeling defects, indicating that Notch1 and Notch4 have partially overlapping essential roles in embryonic vascular morphogenesis.

Abstract

The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the role of the Notch4 gene, we generated Notch4-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene. Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. Both Notch1 mutant and Notch1/Notch4 double mutant embryos displayed severe defects in angiogenic vascular remodeling. Analysis of the expression patterns of genes encoding ligands for Notch family receptors indicated that only the Dll4 gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. These results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling, and indicate that whereas the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice.