Seidl, C. | bioRxiv Science

bioRxiv2022

Primary Cilia are WNT Transducing Organelles whose Biogenesis is Regulated by a WNTPP1 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 {beta}-catenin-dependent gene activation. Here we show that in primary cilia, WNT receptors relay a WNT/GSK3 signal that {beta}-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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/519813v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@4e8f4dorg.highwire.dtl.DTLVardef@1a246f6org.highwire.dtl.DTLVardef@e0df10org.highwire.dtl.DTLVardef@154a139_HPS_FORMAT_FIGEXP M_FIG 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. C_FIG

cell biology↗

bioRxiv2020

R-spondins are BMP receptor antagonists in early embryonic development

BMP signalling plays key roles in development, stem cells, adult tissue homeostasis, and disease. How BMP receptors are extracellularly modulated and in which physiological context, is therefore of prime importance. R-spondins (RSPOs) are a small family of secreted proteins that co-activate WNT signalling and function as potent stem cell effectors and oncogenes. Evidence is mounting that RSPOs act WNT-independently but how and in which physiological processes remains enigmatic. Here we show that RSPO2 and RSPO3 also act as BMP antagonists. RSPO2 is a high affinity ligand for the type I BMP receptor BMPR1A/ALK3, and it engages ZNRF3 to trigger internalization and degradation of BMPR1A. In early Xenopus embryos, Rspo2 is a negative feedback inhibitor in the BMP4 synexpression group and regulates dorsoventral axis formation. We conclude that R-Spondins are bifunctional ligands, which activate WNT- and inhibit BMP signalling via ZNRF3, with implications for development and cancer.

developmental biology↗