Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4073, Australia
The lymphatic system is essential for maintaining homeostasis and immunity. Abnormal development of lymphatic vessels can lead to lymphedema, organ and structure impairment, and immune deficiencies. Knowledge of lymphangiogenesis is valuable for tackling these diseases, but little is known about the molecular regulators of lymphatic network formation, control of branching morphogenesis and cell polarity. We have found that Polycystin-1 knockout in mice leads to defective morphogenesis of developing lymphatic networks and altered polarity of lymphangiogenic sprouts. Polycytin-1 can modulate planar cell polarity pathways and interestingly, we find that mutants in other components of these pathways (Ryk, Wnt5a) show very similar lymphatic defects. Moreover, Polycystin-1 genetically interacts with Wnt5A in lymphangiogenesis. In Polycystin-1 and Wnt5A double knockout mice, the lymphatic network of the dorsal embryonic skin has reduced branch points, loops and migration towards the midline compared with WT and Polycystin-1 knockout mice. Our data show that Polycystin-1 is also required for recruiting core planar cell polarity components. Overall, this study suggests that Polycystin-1 is a novel partner of non-canonical Wnt, planar cell polarity signalling controlling network morphogenesis during lymphangiogenesis.