Pkd1 and Wnt5a genetically interact to control lymphatic vascular morphogenesis in mice

Abstract

Background: Lymphatic vascular development is regulated by wellcharacterized signaling and transcriptional pathways. These pathways regulate lymphatic endothelial cell (LEC) migration, motility, polarity, and morphogenesis. Canonical and non-canonical WNT signaling pathways are known to control LEC polarity and development of lymphatic vessels and valves. PKD1, encoding Polycystin-1, is the most commonly mutated gene in polycystic kidney disease but has also been shown to be essential in lymphatic vascular morphogenesis. The mechanism by which Pkd1 acts during lymphangiogenesis remains unclear.Results: Here we find that loss of non-canonical WNT signaling components Wnt5a and Ryk phenocopy lymphatic defects seen in Pkd1 knockout mice. To investigate genetic interaction, we generated Pkd1;Wnt5a double knockout mice. Loss of Wnt5a suppressed phenotypes seen in the lymphatic vasculature of Pkd1 À/À mice and Pkd1 deletion suppressed phenotypes observed in Wnt5a À/À mice. Thus, we report mutually suppressive roles for Pkd1 and Wnt5a, with developing lymphatic networks restored to a more wild type state in double mutant mice. This genetic interaction between Pkd1 and the

Lymphatic vessel: Origin, heterogeneity, biological functions and therapeutic targets

“… PKD1a partly interacts with WNT5a to regulate LEC sprouting from the horizontal myoseptum. 452 , 453 Synectin A scaffold protein, which regulates LEC sprouting and migration to form TD. Synectin stimulates VEGFR3 and NRP2a to activate downstream signaling.…”