PUBLICATION

Fbxw7 controls angiogenesis by regulating endothelial notch activity

Authors
Izumi, N., Helker, C., Ehling, M., Behrens, A., Herzog, W., and Adams, R.H.
ID
ZDB-PUB-120807-16
Date
2012
Source
PLoS One   7(7): e41116 (Journal)
Registered Authors
Helker, Christian, Herzog, Wiebke
Keywords
Embryos, Notch signaling, Angiogenesis, Zebrafish, Retina, Endothelial cells, Transgenic engineering, Endothelium
MeSH Terms
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Proto-Oncogene Proteins c-myc/genetics
  • Proto-Oncogene Proteins c-myc/metabolism
  • Cell Proliferation/drug effects
  • Cell Cycle Proteins/genetics
  • Cell Cycle Proteins/metabolism*
  • Human Umbilical Vein Endothelial Cells/cytology
  • Human Umbilical Vein Endothelial Cells/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Mice, Transgenic
  • F-Box Proteins/genetics
  • F-Box Proteins/metabolism*
  • Receptors, Notch/genetics
  • Receptors, Notch/metabolism*
  • Humans
  • Mice
  • Ubiquitin-Protein Ligases/genetics
  • Ubiquitin-Protein Ligases/metabolism*
  • Proto-Oncogene Proteins c-jun/genetics
  • Proto-Oncogene Proteins c-jun/metabolism
  • Neovascularization, Physiologic/physiology*
  • Morpholinos/pharmacology
  • Animals
  • Retina/cytology
  • Retina/metabolism
(all 27)
PubMed
22848434 Full text @ PLoS One
Abstract

Notch signaling controls fundamental aspects of angiogenic blood vessel growth including the selection of sprouting tip cells, endothelial proliferation and arterial differentiation. The E3 ubiquitin ligase Fbxw7 is part of the SCF protein complex responsible for the polyubiquitination and thereby proteasomal degradation of substrates such as Notch, c-Myc and c-Jun. Here, we show that Fbxw7 is a critical regulator of angiogenesis in the mouse retina and the zebrafish embryonic trunk, which we attribute to its role in the degradation of active Notch. Growth of retinal blood vessel was impaired and the Notch ligand Dll4, which is also a Notch target, upregulated in inducible and endothelial cell-specific Fbxw7iECKO mutant mice. The stability of the cleaved and active Notch intracellular domain was increased after siRNA knockdown of the E3 ligase in cultured human endothelial cells. Injection of fbxw7 morpholinos interfered with the sprouting of zebrafish intersegmental vessels (ISVs). Arguing strongly that Notch and not other Fbxw7 substrates are primarily responsible for these phenotypes, the genetic inactivation of Notch pathway components reversed the impaired ISV growth in the zebrafish embryo as well as sprouting and proliferation in the mouse retina. Our findings establish that Fbxw7 is a potent positive regulator of angiogenesis that limits the activity of Notch in the endothelium of the growing vasculature.

Genes / Markers
Figures
Figure Gallery (3 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
j16e1
    Point Mutation
    s843TgTransgenic Insertion
      s896TgTransgenic Insertion
        y1TgTransgenic Insertion
          y7TgTransgenic Insertion
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            fbxw7MO2-fbxw7MRPHLNO
            fbxw7MO3-fbxw7MRPHLNO
            1 - 2 of 2
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            Fish
            Antibodies
            Name Type Antigen Genes Isotypes Host Organism
            Ab1-fbxw7polyclonalRabbit
            1 - 1 of 1
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            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            EGFPEFGEGFP
            mCherryEFGmCherry
            1 - 2 of 2
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            Mapping
            No data available