ZFIN ID: ZDB-PUB-190822-13
Evolutionary Differences in the Vegf/Vegfr Code Reveal Organotypic Roles for the Endothelial Cell Receptor Kdr in Developmental Lymphangiogenesis
Vogrin, A.J., Bower, N.I., Gunzburg, M.J., Roufail, S., Okuda, K.S., Paterson, S., Headey, S.J., Stacker, S.A., Hogan, B.M., Achen, M.G.
Date: 2019
Source: Cell Reports   28: 2023-2036.e4 (Journal)
Registered Authors: Hogan, Ben M., Okuda, Kazuhide Shaun, Paterson, Scott
Keywords: Kdr, VEGF, VEGF receptor, Vegfd, developmental biology, lymphangiogenesis, lymphatic, organotypic, vascular biology, zebrafish
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Endothelial Cells/metabolism*
  • Evolution, Molecular*
  • HEK293 Cells
  • Humans
  • Ligands
  • Lymphangiogenesis*
  • Mice
  • Protein Binding
  • Proteolysis
  • Reproducibility of Results
  • Vascular Endothelial Growth Factor C/chemistry
  • Vascular Endothelial Growth Factor C/genetics*
  • Vascular Endothelial Growth Factor C/metabolism
  • Vascular Endothelial Growth Factor Receptor-2/genetics*
  • Vascular Endothelial Growth Factor Receptor-2/metabolism
  • Zebrafish/embryology*
  • Zebrafish/metabolism*
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed: 31433980 Full text @ Cell Rep.
Lymphatic vascular development establishes embryonic and adult tissue fluid balance and is integral in disease. In diverse vertebrate organs, lymphatic vessels display organotypic function and develop in an organ-specific manner. In all settings, developmental lymphangiogenesis is considered driven by vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3), whereas a role for VEGFR2 remains to be fully explored. Here, we define the zebrafish Vegf/Vegfr code in receptor binding studies. We find that while Vegfd directs craniofacial lymphangiogenesis, it binds Kdr (a VEGFR2 homolog) but surprisingly, unlike in mammals, does not bind Flt4 (VEGFR3). Epistatic analyses and characterization of a kdr mutant confirm receptor-binding analyses, demonstrating that Kdr is indispensible for rostral craniofacial lymphangiogenesis, but not caudal trunk lymphangiogenesis, in which Flt4 is central. We further demonstrate an unexpected yet essential role for Kdr in inducing lymphatic endothelial cell fate. This work reveals evolutionary divergence in the Vegf/Vegfr code that uncovers spatially restricted mechanisms of developmental lymphangiogenesis.