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
-
- Animals
- Animals, Genetically Modified
- Arteries/metabolism*
- Embryo, Nonmammalian/metabolism
- Intracellular Signaling Peptides and Proteins
- Membrane Proteins/genetics
- Membrane Proteins/metabolism*
- Mutation
- Neovascularization, Physiologic/physiology*
- Protein Structure, Tertiary/genetics
- Signal Transduction/genetics*
- Vascular Endothelial Growth Factor C/genetics
- Vascular Endothelial Growth Factor C/metabolism*
- Vascular Endothelial Growth Factor Receptor-3/chemistry
- Vascular Endothelial Growth Factor Receptor-3/genetics
- Vascular Endothelial Growth Factor Receptor-3/metabolism*
- Zebrafish/embryology*
- Zebrafish/metabolism*
- PubMed
- 19906867 Full text @ Development
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping