PUBLICATION

Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis

Authors
Le Guen, L., Karpanen, T., Schulte, D., Harris, N.C., Koltowska, K., Roukens, G., Bower, N.I., van Impel, A., Stacker, S.A., Achen, M.G., Schulte-Merker, S., and Hogan, B.M.
ID
ZDB-PUB-140502-15
Date
2014
Source
Development (Cambridge, England)   141(6): 1239-1249 (Journal)
Registered Authors
Hogan, Ben M., Karpanen, Terhi, Le Guen, Ludovic, Schulte-Merker, Stefan, van Impel, Andreas
Keywords
Angiogenesis, Lymphangiogenesis, Lymphedema, Vasculature, Zebrafish
MeSH Terms
  • DNA/genetics
  • Humans
  • Sequence Homology, Amino Acid
  • Lymphangiogenesis/genetics
  • Lymphangiogenesis/physiology*
  • Vascular Endothelial Growth Factor C/genetics
  • Vascular Endothelial Growth Factor C/metabolism*
  • Amino Acid Sequence
  • Sequence Homology, Nucleic Acid
  • Vascular Endothelial Growth Factor Receptor-3/genetics
  • Vascular Endothelial Growth Factor Receptor-3/metabolism*
  • Mice
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Point Mutation
  • Molecular Sequence Data
  • Signal Transduction
  • Base Sequence
  • MAP Kinase Signaling System
  • Animals
  • Gene Expression Regulation, Developmental
  • Amino Acid Substitution
(all 25)
PubMed
24523457 Full text @ Development
Abstract

The VEGFC/VEGFR3 signaling pathway is essential for lymphangiogenesis (the formation of lymphatic vessels from pre-existing vasculature) during embryonic development, tissue regeneration and tumor progression. The recently identified secreted protein CCBE1 is indispensible for lymphangiogenesis during development. The role of CCBE1 orthologs is highly conserved in zebrafish, mice and humans with mutations in CCBE1 causing generalized lymphatic dysplasia and lymphedema (Hennekam syndrome). To date, the mechanism by which CCBE1 acts remains unknown. Here, we find that ccbe1 genetically interacts with both vegfc and vegfr3 in zebrafish. In the embryo, phenotypes driven by increased Vegfc are suppressed in the absence of Ccbe1, and Vegfc-driven sprouting is enhanced by local Ccbe1 overexpression. Moreover, Vegfc- and Vegfr3-dependent Erk signaling is impaired in the absence of Ccbe1. Finally, CCBE1 is capable of upregulating the levels of fully processed, mature VEGFC in vitro and the overexpression of mature VEGFC rescues ccbe1 loss-of-function phenotypes in zebrafish. Taken together, these data identify Ccbe1 as a crucial component of the Vegfc/Vegfr3 pathway in the embryo.

Genes / Markers
Figures
Figure Gallery (10 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hu3613
    Point Mutation
    hu4602
      Point Mutation
      hu4624TgTransgenic Insertion
        hu5055
          Point Mutation
          hu5142
            Point Mutation
            hu5333TgTransgenic Insertion
              hu6124
                Point Mutation
                hu6410
                  Point Mutation
                  hu9228TgTransgenic Insertion
                    hu9282TgTransgenic Insertion
                      1 - 10 of 15
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      ccbe1MO1-ccbe1MRPHLNO
                      dll4MO4-dll4MRPHLNO
                      flt4MO3-flt4MRPHLNO
                      vegfcMO1-vegfcMRPHLNO
                      1 - 4 of 4
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                      Fish
                      Antibodies
                      Orthology
                      Gene Orthology
                      vegfc
                      1 - 1 of 1
                      Show
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      EGFPEFGEGFP
                      GAL4EFGGAL4
                      mCherryEFGmCherry
                      mTurquoiseEFGmTurquoise
                      TagRFPEFGTagRFP
                      YFPEFGYFP
                      1 - 6 of 6
                      Show
                      Mapping
                      No data available