The angiopoietin/Tie signalling pathway is an endothelial-specific receptor tyrosine kinase (RTK) pathway that is important in mammalian cardiovascular development. Although Tie2 is known to mediate the angiopoietin/Tie pathway, the role of Tie1 is still unclear. Here, Hiroyuki Nakajima and colleagues demonstrate that Angiopoietin 1 (Angpt1)/Tie1 signalling is essential for trunk lymphatic development in zebrafish. First, the authors systematically analyse mutants of all angiopoietins and Tie receptors in zebrafish and observe that only angpt1 and tie1 mutants show defects in lymphatic development. Then, they perform in vitro binding assays and find that, among the three zebrafish angiopoietins, only Angpt1 binds to the Tie1 receptor. Live imaging of tie1 mutants shows that Angpt1/Tie1 signalling is important for endothelial cell migration, specification and proliferation. From RNA-sequencing analyses of endothelial cells, the authors identify the transcription factor FOXO1 among the genes downregulated in tie1 mutants and observe that Tie1 inhibits nuclear import of FOXO1. Finally, the authors find that Tie1 signalling regulates lymphatic development, in part through modulating Vegfc/Vegfr3 signalling, another RTK signalling pathway implicated in lymphangiogenesis. Taken together, these findings suggest that Angpt1 acts as a ligand to the Tie1 receptor and uncover the role of Angpt1/Tie1 signalling in zebrafish lymphatic vessel development.
