DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling
Schueler, Markus; Braun, Daniela A; Chandrasekar, Gayathri; Gee, Heon Yung; Klasson, Timothy D.; Halbritter, Jan; Bieder, Andrea; Porath, Jonathan D; Airik, Rannar; Zhou, Weibin; LoTurco, Joseph J; Che, Alicia; Otto, Edgar A; Böckenhauer, Detlef; Sebire, Neil J; Honzik, Tomas; Harris, Peter C; Koon, Sarah J; Gunay-Aygun, Meral; Saunier, Sophie; Zerres, Klaus; Bruechle, Nadina Ortiz; Drenth, Joost P H; Pelletier, Laurence; Tapia-Páez, Isabel; Lifton, Richard P; Giles, R; Kere, Juha; Hildebrandt, Friedhelm
(2015) American Journal of Human Genetics, volume 96, issue 1, pp. 81 - 92
(Article)
Abstract
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
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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.
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Keywords: Adaptor Proteins, Signal Transducing, Animals, Cilia, Computational Biology, Exons, HEK293 Cells, Humans, Kidney, Kidney Diseases, Cystic, Mice, Microscopy, Electron, Transmission, Microtubule-Associated Proteins, Mutation, NIH 3T3 Cells, Phenotype, Phosphoproteins, Wnt Signaling Pathway, Zebrafish, beta Catenin, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN: 0002-9297
Publisher: Cell Press
Note: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
(Peer reviewed)