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DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling
M. Schueler, DA. Braun, G. Chandrasekar, HY. Gee, TD. Klasson, J. Halbritter, A. Bieder, JD. Porath, R. Airik, W. Zhou, JJ. LoTurco, A. Che, EA. Otto, D. Böckenhauer, NJ. Sebire, T. Honzik, PC. Harris, SJ. Koon, M. Gunay-Aygun, S. Saunier, K....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
NLK
Cell Press Free Archives
od 1997-01-01 do Před 6 měsíci
Free Medical Journals
od 1949 do Před 6 měsíci
PubMed Central
od 1949 do Před 6 měsíci
Europe PubMed Central
od 1949 do Před 6 měsíci
Open Access Digital Library
od 2005-01-01
- MeSH
- adaptorové proteiny signální transdukční genetika metabolismus MeSH
- beta-katenin antagonisté a inhibitory metabolismus MeSH
- buňky NIH 3T3 MeSH
- cilie genetika patologie MeSH
- cystická onemocnění ledvin genetika MeSH
- dánio pruhované genetika MeSH
- exony MeSH
- fenotyp MeSH
- fosfoproteiny genetika metabolismus MeSH
- HEK293 buňky MeSH
- ledviny patologie MeSH
- lidé MeSH
- mutace MeSH
- myši MeSH
- proteiny asociované s mikrotubuly genetika metabolismus MeSH
- signální dráha Wnt genetika MeSH
- transmisní elektronová mikroskopie MeSH
- výpočetní biologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
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.
Department of Biosciences and Nutrition Karolinska Institutet 14183 Huddinge Sweden
Department of Genetics Yale University School of Medicine New Haven CT 06510 USA
Department of Histopathology Great Ormond Street Hospital London WC1N3JH UK
Department of Medicine Boston Children's Hospital Harvard Medical School Boston MA 02115 USA
Department of Molecular Genetics University of Toronto Toronto Ontario M5S 1A8 Canada
Department of Pediatrics and Communicable Diseases University of Michigan Ann Arbor MI 48109 USA
Department of Physiology and Neurobiology University of Connecticut Storrs CT 06269 USA
Division of Nephrology and Hypertension Mayo Clinic Rochester MN 55905 USA
Howard Hughes Medical Institute Chevy Chase MD 20815 USA
Inserm U574 and Department of Genetics Paris 5 University Necker Hospital 75015 Paris France
Institute of Human Genetics University Hospital RWTH Aachen 52074 Aachen Germany
Science for Life Laboratory Karolinska Institutet 171 21 Solna Sweden
Citace poskytuje Crossref.org
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- $a 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.
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