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Nat Cell Biol January 1, 2016; 18 (7): 752-764.

The polycystin complex mediates Wnt/Ca(2+) signalling.

Kim S , Nie H , Nesin V , Tran U , Outeda P , Bai CX , Keeling J , Maskey D , Watnick T , Wessely O , Tsiokas L .

WNT ligands induce Ca(2+) signalling on target cells. PKD1 (polycystin 1) is considered an orphan, atypical G-protein-coupled receptor complexed with TRPP2 (polycystin 2 or PKD2), a Ca(2+)-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 Ca(2+) 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 Ca(2+) 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/Ca(2+) signalling as one of the causes of ADPKD.

PubMed ID: 27214281
PMC ID: PMC4925210
Article link: Nat Cell Biol
Grant support: P30 DK090868 NIDDK NIH HHS , R01 DK059599 NIDDK NIH HHS , R01 DK095036 NIDDK NIH HHS , R01 DK080745 NIDDK NIH HHS , R56 DK059599 NIDDK NIH HHS

Genes referenced: dvl2 pkd1 pkd2 wnt9a wnt9b

Morpholinos referenced: dvl2 MO1 pkd1 MO1 pkd1 MO2 wnt9a MO1

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