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Published on: December 2, 2014
DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling
Markus Schueler1, Daniela A Braun1, Gayathri Chandrasekar2
1Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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.
Insights
Mutations in DCDC2 cause nephronophthisis-related ciliopathies (NPHP-RC), impacting kidney and liver function. Restoring Wnt signaling offers a potential therapeutic strategy for these genetic disorders.
Area of Science:
- Genetics
- Cell Biology
- Developmental Biology
Background:
- Nephronophthisis-related ciliopathies (NPHP-RC) are inherited disorders causing kidney and liver damage.
- The genetic basis and cellular mechanisms underlying NPHP-RC require further elucidation.
Purpose of the Study:
- To identify novel genetic causes of NPHP-RC.
- To investigate the cellular function of DCDC2 in ciliogenesis and Wnt signaling.
- To explore therapeutic targets for NPHP-RC.
Main Methods:
- Genetic analysis of NPHP-RC patients.
- Cellular studies using IMCD3 cells (knockdown, rescue experiments).
- Zebrafish model for NPHP-RC phenotypes.
- Analysis of DCDC2 interaction with DVL and Wnt signaling pathway.
Main Results:
- Mutations in DCDC2 were identified as a cause of renal-hepatic ciliopathy.
- DCDC2 is crucial for ciliogenesis and interacts with DVL.
- DCDC2 mutations impair Wnt signaling inhibition, unlike wild-type DCDC2.
- Wnt signaling inhibition rescues ciliogenesis defects in vitro and NPHP-RC phenotypes in zebrafish.
Conclusions:
- DCDC2 plays a critical role in ciliogenesis and Wnt signaling.
- Dysregulation of Wnt signaling is central to NPHP-RC pathogenesis.
- Targeting Wnt signaling presents a potential therapeutic avenue for NPHP-RC.
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