RT Journal Article
SR Electronic
T1 Pkd1 and Wnt5a genetically interact to control lymphatic vascular morphogenesis in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.31.437795
DO 10.1101/2021.03.31.437795
A1 Tevin CY. Chau
A1 Sungmin Baek
A1 Baptiste Coxam
A1 Renae Skoczylas
A1 Maria Rondon-Galeano
A1 Neil I. Bower
A1 Elanor N. Wainwright
A1 Steven SA. Stacker
A1 Helen M. Cooper
A1 Anne K. Lagendijk
A1 Natasha L. Harvey
A1 Mathias François
A1 Benjamin M. Hogan
YR 2021
UL http://biorxiv.org/content/early/2021/04/01/2021.03.31.437795.abstract
AB Lymphatic vascular development is regulated by well-characterised signalling and transcriptional pathways. These pathways regulate lymphatic endothelial cell (LEC) migration, motility, polarity and and morphogenesis. Canonical and non-canonical WNT signalling 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. Here we find that loss of non-canonical WNT signalling 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−/− mice and Pkd1 deletion suppressed phenotypes observed in Wnt5a−/− 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 non-canonical WNT signalling pathway ultimately controls LEC polarity and the morphogenesis of developing vessel networks. Our work suggests that Pkd1 acts at least in part by regulating non-canonical WNT signalling during the formation of lymphatic vascular networks.Competing Interest StatementThe authors have declared no competing interest.