91 126

Cited 31 times in

DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling

Authors
 Markus Schueler  ;  Daniela A. Braun  ;  Gayathri Chandrasekar  ;  Heon Yung Gee  ;  Timothy D. Klasson  ;  Jan Halbritter  ;  Andrea Bieder  ;  Jonathan D. Porath  ;  Rannar Airik  ;  Weibin Zhou  ;  Joseph J. LoTurco  ;  Alicia Che  ;  Edgar A. Otto  ;  Detlef Bo¨ckenhauer  ;  Neil J. Sebire  ;  Tomas Honzik  ;  Peter C. Harris  ;  Sarah J. Koon  ;  Meral Gunay-Aygun  ;  Sophie Saunier  ;  Klaus Zerres  ;  Nadina Ortiz Bruechle  ;  Joost P.H. Drenth  ;  Laurence Pelletier  ;  Isabel Tapia-Pa´ez  ;  Richard P. Lifton  ;  Rachel H. Giles  ;  Juha Kere  ;  Friedhelm Hildebrandt 
Citation
 AMERICAN JOURNAL OF HUMAN GENETICS, Vol.96(1) : 81-92, 2015 
Journal Title
 AMERICAN JOURNAL OF HUMAN GENETICS 
ISSN
 0002-9297 
Issue Date
2015
MeSH
Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Cilia/genetics ; Cilia/pathology ; Computational Biology ; Dishevelled Proteins ; Exons ; HEK293 Cells ; Humans ; Kidney/pathology ; Kidney Diseases, Cystic/genetics* ; Mice ; Microscopy, Electron, Transmission ; Microtubule-Associated Proteins/genetics* ; Microtubule-Associated Proteins/metabolism ; Mutation ; NIH 3T3 Cells ; Phenotype ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Wnt Signaling Pathway/genetics* ; Zebrafish/genetics ; beta Catenin/antagonists & inhibitors ; beta Catenin/metabolism
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 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.
Files in This Item:
T201504423.pdf Download
DOI
10.1016/j.ajhg.2014.12.002
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/156710
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse