Notch signaling is essential for vascular morphogenesis in mice
- Luke T. Krebs1,
- Yingzi Xue1,5,
- Christine R. Norton1,
- John R. Shutter2,
- Maureen Maguire1,6,
- John P. Sundberg1,
- Daniel Gallahan3,
- Violaine Closson4,
- Jan Kitajewski4,
- Robert Callahan3,
- Gilbert H. Smith3,
- Kevin L. Stark2, and
- Thomas Gridley1,7
- 1The Jackson Laboratory, Bar Harbor, Maine 04609 USA; 2Department of Molecular Genetics, Amgen, Inc., Thousand Oaks, California 91320 USA; 3Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892 USA; 4Department of Pathology and Obstetrics and Gynecology, Columbia University, College of Physicians and Surgeons, New York, New York 10032 USA
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 generatedNotch4-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 relatedNotch1 gene. Embryos homozygous for mutations of both theNotch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. BothNotch1 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 Dll4gene 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 theNotch4 gene is not essential during embryonic development, theNotch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice.
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Footnotes
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Present addresses: 5Skirball Institute of Bimolecular Medicine, New York University Medical Center, New York, New York 10016 USA; 6Schering-Plogh Research Institute, Kenilworth, New Jersey 07033 USA.
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↵7 Corresponding author.
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E-MAIL gridley{at}jax.org; FAX 207-288-6077.
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- Received December 16, 1999.
- Accepted March 23, 2000.
- Cold Spring Harbor Laboratory Press
