Primary Cilia are WNT Transducing Organelles whose Biogenesis is Regulated by a WNT┫ PP1 axis

WNT signalling is of paramount importance in development, stem cell maintenance, and disease. WNT ligands typically signal via receptor activation at the plasma membrane to induce β-catenin-dependent gene activation. Here we show that in primary cilia, WNT receptors relay a WNT/GSK3 signal that β-catenin-independently promotes ciliogenesis. Innovations supporting this conclusion are monitoring acute WNT co-receptor activation (phospho-LRP6) and identifying and mutating the LRP6 ciliary targeting sequence. Ciliary WNT signalling inhibits protein phosphatase 1 (PP1) activity, a negative regulator of ciliogenesis, by decommissioning GSK3-mediated phosphorylation of the PP1 regulatory inhibitor subunit PPP1R2. Accordingly, deficiency of WNT/GSK3 signalling by depletion of cyclin Y and cyclin-Y-like protein 1 induces widespread primary cilia defects in mouse embryonic neuronal precursors, kidney proximal tubules, and adult mice preadipocytes. We conclude that primary cilia are WNT ┫ PP1 signalling organelles. Graphical Abstract A Localized WNT ┫ PP1 Signalling Axis Promotes Ciliogenesis The WNT co-receptor LRP6 localizes to the ciliary membrane, where it is phospho-primed via a CCNY/L1-dependent CDK (not shown). WNT signalling inhibits GSK3 (not shown) and leads to inhibition of Protein phosphatase 1, a negative regulator of ciliogenesis. Right, CCNY/L1 deficiency disrupts the WNT ┫ PP1 signalling axis, leading to ciliary defects.