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

Hogan, Benjamin M., Herpers, Robert, Witte, Merlijn, Helotera, Hanna, Alitalo, Kari, Duckers, Hendricus J. and Schulte-Merker, Stefan (2009) Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries. Development, 136 23: 4001-4009. doi:10.1242/dev.039990

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Author Hogan, Benjamin M.
Herpers, Robert
Witte, Merlijn
Helotera, Hanna
Alitalo, Kari
Duckers, Hendricus J.
Schulte-Merker, Stefan
Title Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries
Journal name Development   Check publisher's open access policy
ISSN 0950-1991
Publication date 2009-09-25
Year available 2009
Sub-type Article (original research)
DOI 10.1242/dev.039990
Open Access Status File (Publisher version)
Volume 136
Issue 23
Start page 4001
End page 4009
Total pages 9
Place of publication Cambridge, United Kingdom
Publisher The Company of Biologists Ltd.
Language eng
Subject 1309 Developmental Biology
1312 Molecular Biology
Formatted 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. 
Keyword Arterial
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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