Notch signaling is essential for vascular morphogenesis in mice

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Abstract
The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the role of theNotch4gene, we generatedNotch4-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, theNotch4mutation displayed genetic interactions with a targeted mutation of the relatedNotch1gene. Embryos homozygous for mutations of both theNotch4andNotch1genes often displayed a more severe phenotype thanNotch1homozygous mutant embryos. BothNotch1mutant andNotch1/Notch4double 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 theDll4gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for theNotch1andNotch4receptors 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 theNotch4gene is not essential during embryonic development, theNotch4andNotch1genes have partially overlapping roles during embryogenesis in mice.