PUBLICATION

Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries

Authors
Hogan, B.M., Herpers, R., Witte, M., Heloterä, H., Alitalo, K., Duckers, H.J., and Schulte-Merker, S.
ID
ZDB-PUB-091120-46
Date
2009
Source
Development (Cambridge, England)   136(23): 4001-4009 (Journal)
Registered Authors
Herpers, Robert, Hogan, Ben M., Schulte-Merker, Stefan, Witte, Merlijn
Keywords
Dll4, Flt4, Vegfc, Arterial, Lymphatics, Zebrafish
MeSH Terms
  • Intracellular Signaling Peptides and Proteins
  • Animals
  • Arteries/metabolism*
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism*
  • Animals, Genetically Modified
  • Protein Structure, Tertiary/genetics
  • Mutation
  • Zebrafish/embryology*
  • Zebrafish/metabolism*
  • Signal Transduction/genetics*
  • Neovascularization, Physiologic/physiology*
  • Vascular Endothelial Growth Factor C/genetics
  • Vascular Endothelial Growth Factor C/metabolism*
  • Embryo, Nonmammalian/metabolism
  • Vascular Endothelial Growth Factor Receptor-3/chemistry
  • Vascular Endothelial Growth Factor Receptor-3/genetics
  • Vascular Endothelial Growth Factor Receptor-3/metabolism*
(all 18)
PubMed
19906867 Full text @ Development
Abstract
The development of arteries, veins and lymphatics from pre-existing vessels are intimately linked processes controlled by a number of well-studied reiteratively acting signalling pathways. To delineate the mechanisms governing vessel formation in vivo, we performed a forward genetic screen in zebrafish and isolated the mutant expando. Molecular characterisation revealed a loss-of-function mutation in the highly conserved kinase insert region of flt4. Consistent with previous reports, flt4 mutants were deficient in lymphatic vascular development. Recent studies have demonstrated a role for Flt4 in blood vessels and showed that Dll4 limits angiogenic potential by limiting Flt4 function in developing blood vessels. We found that arterial angiogenesis proceeded normally, yet the dll4 loss-of-function arterial hyperbranching phenotype was rescued, in flt4 signalling mutants. Furthermore, we found that the Flt4 ligand Vegfc drives arterial hyperbranching in the absence of dll4. Upon knockdown of dll4, intersegmental arteries were sensitised to increased vegfc levels and the overexpression of dll4 inhibited Vegfc/Flt4-dependent angiogenesis events. Taken together, these data demonstrate that dll4 functions to suppress the ability of developing intersegmental arteries to respond to Vegfc-driven Flt4 signalling in zebrafish. We propose that this mechanism contributes to the differential response of developing arteries and veins to a constant source of Vegfc present in the embryo during angiogenesis.
Genes / Markers
Figures
Figure Gallery (9 images)
Show all Figures
Expression
Phenotype
Fish Conditions Stage Phenotype Figure
flt4hu4602/hu4602; hu4624Tgstandard conditionsProtruding-mouth
flt4hu4602/hu4602; hu4624Tg + MO4-dll4standard conditionsProtruding-mouth
flt4hu4602/hu4602; s916Tg; y1Tgstandard conditionsDay 5
flt4hu4602/hu4602; s916Tg; y1Tgstandard conditionsDay 5
flt4hu4602/hu4602; y1Tgstandard conditionsPrim-5
flt4hu4602/hu4602; y1Tgstandard conditionsDay 5
flt4hu4602/hu4602; y1Tgstandard conditionsDay 5
hu4624Tg + MO1-vegfc + MO4-dll4standard conditionsProtruding-mouth
hu4624Tg + MO4-dll4standard conditionsPrim-5
hu4624Tg + MO4-dll4standard conditionsProtruding-mouth
1 - 10 of 20
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
hu4602
    		Point Mutation
    hu4624TgTransgenic Insertion
      hu4881TgTransgenic Insertion
        s916TgTransgenic Insertion
          y1TgTransgenic Insertion
            1 - 5 of 5
            Show
            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            dll4MO4-dll4MRPHLNO
            flt4MO3-flt4MRPHLNO
            vegfcMO1-vegfcMRPHLNO
            1 - 3 of 3
            Show
            Fish
            Fish
            flt4hu4602/hu4602
            flt4hu4602/hu4602; hu4624Tg
            flt4hu4602/hu4602; hu4624Tg + MO4-dll4
            flt4hu4602/hu4602; s916Tg; y1Tg
            flt4hu4602/hu4602; y1Tg
            hu4624Tg
            hu4624Tg + MO1-vegfc + MO4-dll4
            hu4624Tg + MO4-dll4
            hu4881Tg
            hu4881Tg + MO4-dll4
            1 - 10 of 16
            Show
            Antibodies
            No data available
            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            EGFPEFGEGFP
            mCherryEFGmCherry
            YFPEFGYFP
            1 - 3 of 3
            Show
            Mapping
            No data available
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            Citation
            Hogan, B.M., Herpers, R., Witte, M., Heloterä, H., Alitalo, K., Duckers, H.J., and Schulte-Merker, S. (2009) Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries. Development (Cambridge, England). 136(23):4001-4009.