Distinct Genetic Interactions between Multiple Vegf Receptors Are Required for Development of Different Blood Vessel Types in Zebrafish

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 17; pp. 6554 - 6559
• Main Authors: Covassin, L. D., Villefranc, J. A., Kacergis, M. C., Weinstein, B. M., Lawson, N. D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.04.2006
• Subjects: Animals; Aorta; Arteries; Base Sequence; Biological Sciences; Biology; Blood vessels; Blood Vessels - embryology; Blood Vessels - metabolism; Danio rerio; Developmental biology; DNA, Complementary - genetics; Embryos; Endothelial cells; Fish; Gene expression; Genetic mutation; Genetics; Molecular Sequence Data; Mutation; Phenotype; Phylogeny; Receptors; Receptors, Vascular Endothelial Growth Factor - genetics; Receptors, Vascular Endothelial Growth Factor - metabolism; Rodents; Siblings; Vascular Endothelial Growth Factor C - metabolism; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular Endothelial Growth Factor Receptor-3 - genetics; Vascular Endothelial Growth Factor Receptor-3 - metabolism; Veins; Veins & arteries; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• DOI: 10.1073/pnas.0506886103
• ISSN: 0027-8424

Recent evidence indicates a specific role for vascular endothelial growth factor a (Vegfa) during artery development in both zebrafish and mouse embryos, whereas less is known about signals that govern vein formation. In zebrafish, loss of vegfa blocks segmental artery formation and reduces artery-specific gene expression, whereas veins are largely unaffected. Here, we describe a mutation in the zebrafish vegf receptor-2 homolog, kdra, which eliminates its kinase activity and leads to specific defects in artery development. We further find that Fit4, a receptor for Vegfc, cooperates with Kdr during artery morphogenesis, but not differentiation. We also identify an additional zebrafish vegfr-2 ortholog, referred to as kdrb, which can partially compensate for loss of kdra but is dispensable for vascular development in wild-type embryos. Interestingly, we find that these Vegf receptors are also required for formation of veins but in distinct genetic interactions that differ from those required for artery development. Taken together, our results indicate that formation of arteries and veins in the embryo is governed in part by different Vegf receptor combinations and suggest a genetic mechanism for generating blood vessel diversity during vertebrate development.