svep1 and tie1 genetically interact and affect 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 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 of svep1 mutants are also present in tie1, but not in tie2 or vegfc mutants. 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 (DLAV) under reduced flow conditions. Furthermore, we show genetic interaction between svep1 and tie1 during the migration of parachordal lymphangioblasts (PLs). Therefore, our study demonstrates an important function for Tie1 signalling during lymphangiogenesis as well as blood vessel development in zebrafish and provides the first in vivo evidence for zebrafish Svep1 and Tie1 interaction. Since compound heterozygous mutations for SVEP1 and TIE2 have 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.

Polydom/SVEP1 binds to Tie1 and promotes migration of lymphatic endothelial cells

“…Tie1 knockout in zebrafish was also shown to cause severe edema ( Carlantoni et al, 2021 ). Recently, Hußmann et al reported that multiple phenotypic traits in the lymphatic and blood vasculature were shared between tie1 -null and svep1/polydom -null zebrafish, and proposed a genetic interaction between svep1/polydom and tie1 ( Hußmann et al, 2022 Preprint ). It should be noted that defects in venous development were observed in the skin of Polydom-deficient mice but were not observed in the cardinal vein or mesenteries ( Morooka et al, 2017 ).…”

The Relationship between the Secondary Vascular System and the Lymphatic Vascular System in Fish

“…In 2006, Yaniv et al (Yaniv et al, 2006) and Küchler et al (Küchler et al, 2006) described the development of lymphatic vascular network in zebrafish embryos using time-lapse imaging of 6 transgenic zebrafish, molecular markers, and morpholino inhibition experiments of the lymphaticspecific VEGFC/VEGFR3 signalling pathway. Since then, many follow-up publications have contributed to our understanding of the lymphatic development in zebrafish (Hogan et al, 2009a;Bussmann et al, 2010;Le Guen et al, 2014;Nicenboim et al, 2015;Koltowska et al, 2015;Jung et al, 2017;Vogrin et al, 2019;Peng et al, 2022;Hußmann et al, 2023;Grimm et al, 2023).…”