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

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• WNT ligands are crucial signaling molecules.
• Polycystin-1 (PKD1) and TRPP2 form a complex implicated in Autosomal Dominant Polycystic Kidney Disease (ADPKD).
• The precise function of the PKD1-TRPP2 complex in WNT signaling remains unclear.

Purpose of the Study:

• To investigate the interaction between WNT ligands and the PKD1-TRPP2 complex.
• To determine the role of this interaction in calcium (Ca2+) signaling.
• To explore the implications for ADPKD pathogenesis.

Main Methods:

• Binding assays to detect WNT-PKD1 interaction.
• Electrophysiology to measure whole-cell currents and Ca2+ influx.
• Analysis of patient-derived mutations in PKD1 and PKD2.
• Cell migration and polarization assays in fibroblasts.
• Gene manipulation studies in Xenopus embryos.

Main Results:

• WNTs bind to the extracellular domain of PKD1, inducing TRPP2-dependent Ca2+ influx.
• Pathogenic mutations in PKD1 or PKD2 disrupt WNT-induced signaling and complex formation.
• Pkd2-deficient cells exhibit impaired WNT responses and cell polarization.
• PKD1, DVL2, and WNT9A function together in tubulogenesis in Xenopus.

Conclusions:

• PKD1 acts as a WNT (co)receptor, mediating WNT-induced Ca2+ signaling through TRPP2.
• Defects in this WNT/Ca2+ pathway are implicated in the development of ADPKD.
• This finding opens new avenues for understanding and potentially treating ADPKD.