Passa al contenuto
Merck

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

American journal of human genetics (2015-01-06)
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 Böckenhauer, 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-Páez, Richard P Lifton, Rachel H Giles, Juha Kere, Friedhelm Hildebrandt
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.

MATERIALI
N° Catalogo
Marchio
Descrizione del prodotto

Sigma-Aldrich
Anti-CEP164 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-PCNT antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution, Ab2