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First published online November 11, 2009
doi: 10.1242/10.1242/dev.039990

Development 136, 4001-4009 (2009)
Published by The Company of Biologists 2009
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Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries

Benjamin M. Hogan1,*, Robert Herpers1,2,*, Merlijn Witte1, Hanna Heloterä3, Kari Alitalo3, Henricus J. Duckers2 and Stefan Schulte-Merker1,{dagger}

1 Hubrecht Institute-KNAW & University Medical Centre, Utrecht, and Centre for Biomedical Genetics, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
2 Experimental Cardiology, Thoraxcenter, Erasmus University Medical Centre, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
3 Molecular Cancer Biology Laboratory, Department of Pathology, Haartman Institute, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O.B. 63, 00014 Helsinki, Finland

{dagger} Author for correspondence (s.schulte{at}hubrecht.eu)

Accepted October 6, 2009

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.

Key words: Dll4, Flt4, Vegfc, Arterial, Lymphatics, Zebrafish


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