Given that Polydom-knockout mice and zebrafish exhibit defects in lymphatic vessel development and develop severe lymphedema, resembling the phenotypes of Tie1-knockout mice and zebrafish, these findings lead us to conclude that Polydom is a hitherto unidentified ligand for Tie1 that plays an important role in lymphatic vessel development through modulation of the Ang–Tie signaling system. This evidence concerns the gene TIE1 and lymphedema.