title: Duplicate VegfA genes and orthologues of the KDR receptor tyrosine kinase family mediate vascular development in the zebrafish.
abstract: Vascular endothelial growth factor A (VEGFA) and the type III receptor tyrosine kinase receptors (RTKs) are both required for the differentiation of endothelial cells (vasculogenesis) and for the sprouting of new capillaries (angiogenesis). We have isolated a duplicated zebrafish VegfA locus, termed VegfAb, and a duplicate RTK locus with homology to KDR/FLK1 (named Kdrb). Morpholino-disrupted VegfAb embryos develop a normal circulatory system until approximately 2 to 3 days after fertilization (dpf), when defects in angiogenesis permit blood to extravasate into many tissues. Unlike the VegfAa(121) and VegfAa(165) isoforms, the VegfAb isoforms VegfAb(171) and VegfAb(210) are not normally secreted when expressed in mammalian tissue culture cells. The Kdrb locus encodes a 1361-amino acid transmembrane receptor with strong homology to mammalian KDR. Combined knockdown of both RTKs leads to defects in vascular development, suggesting that they cooperate in mediating the vascular effects of VegfA in zebrafish development. Both VegfAa and VegfAb can individually bind and promote phosphorylation of both Flk1 (Kdra) and Kdrb proteins in vitro. Taken together, our data support a model in the zebrafish, in which duplicated VegfA and multiple type III RTKs mediate vascular development.
authors: Department of Medicine, University of Pittsburgh School of Medicine, PA15260, USA. bahary@pitt.edu
authors: Nathan
authors: N
authors: Bahary
authors: Katsutoshi
authors: K
authors: Goishi
authors: Carsten
authors: C
authors: Stuckenholz
authors: Gerhard
authors: G
authors: Weber
authors: Jocelyn
authors: J
authors: Leblanc
authors: Christopher A
authors: CA
authors: Schafer
authors: Sarah S
authors: SS
authors: Berman
authors: Michael
authors: M
authors: Klagsbrun
authors: Leonard I
authors: LI
authors: Zon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D004625:Embryo, Nonmammalian; D020131:Genes, Duplicate; D007527:Isoenzymes / Q000235:genetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000235:genetics; D010802:Phylogeny; D017385:Sequence Homology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000502:physiology; D015027:Zebrafish / Q000235:genetics*
chemical_list: D007527:Isoenzymes; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
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