DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling.
Nephronophthisis-related ciliopathies (NPHP-RC) are recessive diseases characterized by renal dysplasia or degeneration. We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy. DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner. Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations. We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors. Mutations detected in human NPHP-RC lack these effects. A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis. Knockdown of dcdc2 in zebrafish recapitulates NPHP-RC phenotypes, including renal cysts and hydrocephalus, which is rescued by a Wnt inhibitor and by WT, but not by mutant, DCDC2. We thus demonstrate a central role of Wnt signaling in the pathogenesis of NPHP-RC, suggesting an avenue for potential treatment of NPHP-RC.
Schueler, M; Braun, DA; Chandrasekar, G; Gee, HY; Klasson, TD; Halbritter, J; Bieder, A; Porath, JD; Airik, R; Zhou, W; LoTurco, JJ; Che, A; Otto, EA; Böckenhauer, D; Sebire, NJ; Honzik, T; Harris, PC; Koon, SJ; Gunay-Aygun, M; Saunier, S; Zerres, K; Bruechle, NO; Drenth, JPH; Pelletier, L; Tapia-Páez, I; Lifton, RP; Giles, RH; Kere, J; Hildebrandt, F
Volume / Issue
Start / End Page
Electronic International Standard Serial Number (EISSN)
International Standard Serial Number (ISSN)
Digital Object Identifier (DOI)