Svep1 is a binding ligand of Tie1 and affects specific aspects of facial lymphatic development in a Vegfc-independent manner

Abstract

Multiple factors are required to form functional lymphatic vessels. Here, we uncover an essential role for the secreted protein Svep1 and the transmembrane receptor Tie1 during the development of subpopulations of the zebrafish facial lymphatic network. This specific aspect of the facial network forms independently of Vascular endothelial growth factor C (Vegfc) signalling, which otherwise is the most prominent signalling axis in all other lymphatic beds. Additionally, we find that multiple specific and newly uncovered phenotypic hallmarks ofsvep1mutants are also present intie1, but not intie2orvegfcmutants. These phenotypes are observed in the lymphatic vasculature of both head and trunk, as well as in the development of the dorsal longitudinal anastomotic vessel under reduced flow conditions. Therefore, our study demonstrates an important function for Tie1 signalling during lymphangiogenesis as well as blood vessel development in zebrafish. Furthermore, we show genetic interaction betweensvep1andtie1in vivo, during early steps of lymphangiogenesis, and demonstrate that zebrafish as well as human Svep1/SVEP1 protein bind to the respective Tie1/TIE1 receptors in vitro. Since compound heterozygous mutations forSVEP1andTIE2have recently been reported in human glaucoma patients, our data have clinical relevance in demonstrating a role for SVEP1 in TIE signalling in an in vivo setting.