Document Detail


Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries.
MedLine Citation:
PMID:  19906867     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Benjamin M Hogan; Robert Herpers; Merlijn Witte; Hanna Heloter??; Kari Alitalo; Henricus J Duckers; Stefan Schulte-Merker
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  136     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-11-12     Completed Date:  2009-12-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  4001-9     Citation Subset:  IM    
Affiliation:
Hubrecht Institute-KNAW & University Medical Centre, Utrecht, and Centre for Biomedical Genetics, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Genetically Modified
Arteries / metabolism*
Embryo, Nonmammalian / metabolism
Membrane Proteins / genetics,  metabolism*
Mutation
Neovascularization, Physiologic / physiology*
Protein Structure, Tertiary / genetics
Signal Transduction / genetics*
Vascular Endothelial Growth Factor C / genetics,  metabolism*
Vascular Endothelial Growth Factor Receptor-3 / chemistry,  genetics,  metabolism*
Zebrafish / embryology*,  metabolism*
Chemical
Reg. No./Substance:
0/Membrane Proteins; 0/Vascular Endothelial Growth Factor C; 0/delta protein; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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