title: Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development.
abstract: 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.
authors.affiliation: Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Neil I
authors.initials: NI
authors.lastname: Bower
authors.affiliation: Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Vogrin
authors.affiliation: Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Le Guen
authors.affiliation: Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Huijun
authors.initials: H
authors.lastname: Chen
authors.affiliation: Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.affiliation: Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Achen
authors.affiliation: Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia b.hogan@imb.uq.edu.au.
authors.forename: Benjamin M
authors.identifier: 0000-0002-0651-7065
authors.initials: BM
authors.lastname: Hogan
mesh_terms: D000818:Animals; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008954:Models, Biological; D016296:Mutagenesis; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D015398:Signal Transduction; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000502:physiology; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000502:physiology; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D029961:Zebrafish Proteins; C064045:delta protein; C493178:vascular endothelial growth factor C, zebrafish; C000590871:vascular endothelial growth factor D, zebrafish; C583603:FLT1 protein, zebrafish; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C000595917:kdr protein, zebrafish
keywords: Flt4; Kdr; Lymphangiogenesis; Lymphatic; Vegfc; Vegfd