DCDC2 Mutations Cause a Renal-Hepatic Ciliopathy by Disrupting Wnt Signaling

Am J Hum Genet. 2015 Jan 8;96(1):81-92. doi: 10.1016/j.ajhg.2014.12.002. Epub 2014 Dec 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Adaptor Proteins, Signal Transducing
  • DCDC2 protein, human
  • DCDC2 protein, mouse
  • Dishevelled Proteins
  • Microtubule-Associated Proteins
  • Phosphoproteins
  • beta Catenin