Evolutionary Differences in the Vegf/Vegfr Code Reveal Organotypic Roles for the Endothelial Cell Receptor Kdr in Developmental Lymphangiogenesis
Adam J. Vogrin,
Neil I. Bower,
Menachem J. Gunzburg,
Sally Roufail,
Kazuhide S. Okuda,
Scott Paterson,
Stephen J. Headey,
Steven A. Stacker,
Benjamin M. Hogan,
Marc G. Achen
Affiliations
Adam J. Vogrin
Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Neil I. Bower
Division of Genomics of Development and Disease, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia
Menachem J. Gunzburg
Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia
Sally Roufail
Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Kazuhide S. Okuda
Division of Genomics of Development and Disease, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia
Scott Paterson
Division of Genomics of Development and Disease, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia
Stephen J. Headey
Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia
Steven A. Stacker
Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Department of Surgery, Royal Melbourne Hospital, and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia
Benjamin M. Hogan
Division of Genomics of Development and Disease, Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia; Corresponding author
Marc G. Achen
Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Department of Surgery, Royal Melbourne Hospital, and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia; Corresponding author
Summary: Lymphatic vascular development establishes embryonic and adult tissue fluid balance and is integral in disease. In diverse vertebrate organs, lymphatic vessels display organotypic function and develop in an organ-specific manner. In all settings, developmental lymphangiogenesis is considered driven by vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3), whereas a role for VEGFR2 remains to be fully explored. Here, we define the zebrafish Vegf/Vegfr code in receptor binding studies. We find that while Vegfd directs craniofacial lymphangiogenesis, it binds Kdr (a VEGFR2 homolog) but surprisingly, unlike in mammals, does not bind Flt4 (VEGFR3). Epistatic analyses and characterization of a kdr mutant confirm receptor-binding analyses, demonstrating that Kdr is indispensible for rostral craniofacial lymphangiogenesis, but not caudal trunk lymphangiogenesis, in which Flt4 is central. We further demonstrate an unexpected yet essential role for Kdr in inducing lymphatic endothelial cell fate. This work reveals evolutionary divergence in the Vegf/Vegfr code that uncovers spatially restricted mechanisms of developmental lymphangiogenesis. : Lymphatic vessels display organotypic function and develop in an organ-specific manner. Vogrin et al. find that the zebrafish Kdr receptor is indispensible for craniofacial, but not trunk, lymphangiogenesis whereas Flt4 is essential for the latter. Thus, vascular endothelial growth factor (VEGF) receptor signaling pathways are differentially employed in different tissues to drive developmental lymphangiogenesis. Keywords: developmental biology, Kdr, lymphangiogenesis, lymphatic, organotypic, vascular biology, VEGF, VEGF receptor, Vegfd, zebrafish
