The polycystin complex mediates Wnt/Ca2+ signalling

Abstract

WNT ligands induce Ca2+ signaling on target cells. PKD1 (Polycystin 1) is considered an orphan, atypical G protein coupled receptor complexed with TRPP2 (Polycystin 2 or PKD2), a Ca2+-permeable ion channel. Inactivating mutations in their genes cause autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases. Here, we show that WNTs bind to the extracellular domain of PKD1 and induce whole cell currents and Ca2+ influx dependent on TRPP2. Pathogenic PKD1 or PKD2 mutations that abrogate complex formation, compromise cell surface expression of PKD1, or reduce TRPP2 channel activity suppress activation by WNTs. Pkd2−/− fibroblasts lack WNT-induced Ca2+ currents and are unable to polarize during directed cell migration. In Xenopus embryos, PKD1, Dishevelled 2 (DVL2), and WNT9A act within the same pathway to preserve normal tubulogenesis. These data define PKD1 as a WNT (co)receptor and implicate defective WNT/Ca2+ signaling as one of the causes of ADPKD.

Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD

“…The renal tissues in Vil Cre Pkd2 f/f mice have elevated levels of active, nuclear, and total β-catenin (Ctnnb1) proteins ( Figure 1, A and B) and Axin2, c-Myc, and cyclin D1 proteins, which are produced by Wnt target genes ( Figure 1, C and D), compared with control mice (Pkd2 f/f ). These results are consistent with previous reports that PC2 deficiency increases Wnt/β-catenin signaling (27,37,66 Figure 2A). The loss of one Ctnnb1 allele rescued the elevated levels of active, nuclear, and total β-catenin found in the kidneys of Vil Cre Pkd2 f/f mice, bringing the levels down almost to those of control Pkd2 f/f mice, which did not have Vil-Cre ( Figure 1, A and B).…”

“…Previous studies showed that PC2 in association with Wnt signaling induces calcium influx and that the loss of PC2 disturbs polarization during directional cell migration (27,37,76). The present study demonstrated the importance of elevated Wnt/β-catenin signaling in the polycystic kidney disease phenotypes caused by a Pkd2 loss-of-function mutation in mice.…”

“…Furthermore, we observed a synergistic effect on the canonical Wnt signaling when Pkd2 −/− cells were treated with a Ca 2+ chelator. These results suggested that Ca 2+ participates in the PC2 deficiency-induced activation of canonical Wnt signaling (27).…”

“…Both Wnt signaling pathways have been proposed to have a link to ADPKD progression in animal models and human patients (20,21,(23)(24)(25). Hitherto, many reports have shown that renal cystic disease may result from dysregulation of the noncanonical Wnt pathway by disrupting Wnt/ Ca 2+ signaling and/or PCP processes in renal epithelial cells (23,(26)(27)(28)(29)(30)(31)(32). The roles of canonical Wnt signaling in pathogenesis of ADPKD remain to be unequivocally defined.…”

Isolated polycystic liver disease genes define effectors of polycystin-1 function

“…A recent study proposed that PC1 is a coreceptor for noncanonical Wnt signaling (47). These data may suggest an indirect functional ) loss-of-function alleles (nonsense, frameshift, splice site) was compared with the expected burden independent of ethnicity, and that in the European subset of discovery cohort cases (n = 92) was compared with that in European controls (n = 3,274) using existing scripts and statistical tests listed below.…”