Distinct genetic interactions between multiple Vegf receptors are required for development of different blood vessel types in zebrafish

Covassin, L.D., Villefranc, J.A., Kacergis, M.C., Weinstein, B.M., and Lawson, N.D.
Proceedings of the National Academy of Sciences of the United States of America   103(17): 6554-6559 (Journal)
Registered Authors
Covassin, Laurence, Kacergis, Michael C., Lawson, Nathan, Villefranc, Jacque, Weinstein, Brant M.
differentiation, endothelial
MeSH Terms
  • Animals
  • Base Sequence
  • Blood Vessels/embryology*
  • Blood Vessels/metabolism*
  • DNA, Complementary/genetics
  • Molecular Sequence Data
  • Mutation
  • Phenotype
  • Phylogeny
  • Receptors, Vascular Endothelial Growth Factor/genetics*
  • Receptors, Vascular Endothelial Growth Factor/metabolism
  • 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
  • Zebrafish/embryology*
  • Zebrafish/genetics*
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
16617120 Full text @ Proc. Natl. Acad. Sci. USA
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 Flt4, 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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes