Evolutionary differences in the Vegf/Vegfr code reveal organotypic roles for the endothelial cell receptor Kdr in developmental lymphangiogenesis

Lymphatic vascular development establishes embryonic and adult tissue fluid balance and is integralin disease. In diverse vertebrate organs, lymphatic vessels display organotypic function and develop inan organ-specific manner. In all settings, developmental lymphangiogenesis is considered driven byVEGF receptor-3 (VEGFR3), whereas a role for VEGFR2 remains to be fully explored. Here, wedefine the zebrafish Vegf/Vegfr code in receptor binding studies. We find that while Vegfd directscraniofacial lymphangiogenesis, it binds Kdr (a VEGFR2 homologue) but surprisingly, unlike inmammals, does not bind Flt4 (VEGFR3). Epistatic analyses and characterization of a kdr mutantconfirm receptor binding analyses demonstrating that Kdr is indispensible for rostral craniofaciallymphangiogenesis, but not caudal trunk lymphangiogenesis in which Flt4 is central. We furtherdemonstrate an unexpected yet essential role for Kdr in inducing lymphatic endothelial cell fate. Thiswork reveals evolutionary divergence in the Vegf/Vegfr code that uncovers spatially-restrictedmechanisms of developmental lymphangiogenesis.