Journal
DEVELOPMENT
Volume 144, Issue 3, Pages 507-518Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.146969
Keywords
Vegfd; Vegfc; Flt4; Kdr; Lymphatic; Lymphangiogenesis
Categories
Funding
- National Health and Medical Research Council of Australia
- National Health and Medical Research Council/National Heart Foundation of Australia Career Development Fellowship [100442, 1083811]
- [1050138]
- [1053535]
- [1042460]
- National Health and Medical Research Council of Australia [1083811] Funding Source: NHMRC
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Vascular endothelial growth factors (VEGFs) control angiogenesis and lymphangiogenesis during development and in pathological conditions. In the zebrafish trunk, Vegfa controls the formation of intersegmental arteries by primary angiogenesis and Vegfc is essential for secondary angiogenesis, giving rise to veins and lymphatics. Vegfd has been largely thought of as dispensable for vascular development in vertebrates. Here, we generated a zebrafish vegfd mutant by genome editing. vegfd mutants display significant defects in facial lymphangiogenesis independent of vegfc function. Strikingly, we find that vegfc and vegfd cooperatively control lymphangiogenesis throughout the embryo, including during the formation of the trunk lymphatic vasculature. Interestingly, we find that vegfd and vegfc also redundantly drive artery hyperbranching phenotypes observed upon depletion of Flt1 or Dll4. Epistasis and biochemical binding assays suggest that, during primary angiogenesis, Vegfd influences these phenotypes through Kdr (Vegfr2) rather than Flt4 (Vegfr3). These data demonstrate that, rather than being dispensable during development, Vegfd plays context-specific indispensable and also compensatory roles during both blood vessel angiogenesis and lymphangiogenesis.
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