PUBLICATION

Evolutionary Differences in the Vegf/Vegfr Code Reveal Organotypic Roles for the Endothelial Cell Receptor Kdr in Developmental Lymphangiogenesis

Authors
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.
ID
ZDB-PUB-190822-13
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
  • Animals
  • Proteolysis
  • Protein Binding
  • Vascular Endothelial Growth Factor C/chemistry
  • Vascular Endothelial Growth Factor C/genetics*
  • Vascular Endothelial Growth Factor C/metabolism
  • Evolution, Molecular*
  • Reproducibility of Results
  • Vascular Endothelial Growth Factor Receptor-2/genetics*
  • Vascular Endothelial Growth Factor Receptor-2/metabolism
  • Lymphangiogenesis*
  • HEK293 Cells
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Zebrafish/embryology*
  • Zebrafish/metabolism*
  • Mice
  • Ligands
  • Humans
  • Endothelial Cells/metabolism*
  • Amino Acid Sequence
(all 22)
PubMed
31433980 Full text @ Cell Rep.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ci5TgTransgenic Insertion
    hu4602
      Point Mutation
      nz101TgTransgenic Insertion
        uq38bh
          Insertion
          uq42bhTgTransgenic Insertion
            y1TgTransgenic Insertion
              y7TgTransgenic Insertion
                1 - 7 of 7
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                kdrCRISPR1-kdrCRISPR
                1 - 1 of 1
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                Fish
                Antibodies
                Name Type Antigen Genes Isotypes Host Organism
                Ab5-prox1polyclonalIgGRabbit
                1 - 1 of 1
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                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                DsRedEFGDsRed
                EGFPEFGEGFP
                EYFPEFGEYFP
                mCherryEFGmCherry
                1 - 4 of 4
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                Mapping
                No data available