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

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; R Giles; Juha Kere; Friedhelm Hildebrandt

doi:10.1016/j.ajhg.2014.12.002

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

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 SaunierKlaus Zerres, Nadina Ortiz Bruechle, Joost P H Drenth, Laurence Pelletier, Isabel Tapia-Páez, Richard P Lifton, R Giles, Juha Kere, Friedhelm Hildebrandt

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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.

Original language	English
Pages (from-to)	81-92
Number of pages	12
Journal	American Journal of Human Genetics
Volume	96
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2014.12.002
Publication status	Published - 8 Jan 2015

Keywords

Adaptor Proteins, Signal Transducing
Animals
Cilia
Computational Biology
Exons
HEK293 Cells
Humans
Kidney
Kidney Diseases, Cystic
Mice
Microscopy, Electron, Transmission
Microtubule-Associated Proteins
Mutation
NIH 3T3 Cells
Phenotype
Phosphoproteins
Wnt Signaling Pathway
Zebrafish
beta Catenin

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Schueler, M., Braun, D. A., Chandrasekar, G., Gee, H. Y., Klasson, T. D., Halbritter, J., Bieder, A., Porath, J. D., Airik, R., Zhou, W., LoTurco, J. J., Che, A., Otto, E. A., Böckenhauer, D., Sebire, N. J., Honzik, T., Harris, P. C., Koon, S. J., Gunay-Aygun, M., ... Hildebrandt, F. (2015). DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling. American Journal of Human Genetics, 96(1), 81-92. https://doi.org/10.1016/j.ajhg.2014.12.002

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title = "DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling",

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.",

keywords = "Adaptor Proteins, Signal Transducing, Animals, Cilia, Computational Biology, Exons, HEK293 Cells, Humans, Kidney, Kidney Diseases, Cystic, Mice, Microscopy, Electron, Transmission, Microtubule-Associated Proteins, Mutation, NIH 3T3 Cells, Phenotype, Phosphoproteins, Wnt Signaling Pathway, Zebrafish, beta Catenin",

author = "Markus Schueler and Braun, {Daniela A} and Gayathri Chandrasekar and Gee, {Heon Yung} and Klasson, {Timothy D.} and Jan Halbritter and Andrea Bieder and Porath, {Jonathan D} and Rannar Airik and Weibin Zhou and LoTurco, {Joseph J} and Alicia Che and Otto, {Edgar A} and Detlef B{\"o}ckenhauer and Sebire, {Neil J} and Tomas Honzik and Harris, {Peter C} and Koon, {Sarah J} and Meral Gunay-Aygun and Sophie Saunier and Klaus Zerres and Bruechle, {Nadina Ortiz} and Drenth, {Joost P H} and Laurence Pelletier and Isabel Tapia-P{\'a}ez and Lifton, {Richard P} and R Giles and Juha Kere and Friedhelm Hildebrandt",

year = "2015",

month = jan,

day = "8",

doi = "10.1016/j.ajhg.2014.12.002",

language = "English",

volume = "96",

pages = "81--92",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

Schueler, M, Braun, DA, Chandrasekar, G, Gee, HY, Klasson, TD, Halbritter, J, Bieder, A, Porath, JD, Airik, R, Zhou, W, LoTurco, JJ, Che, A, Otto, EA, Böckenhauer, D, Sebire, NJ, Honzik, T, Harris, PC, Koon, SJ, Gunay-Aygun, M, Saunier, S, Zerres, K, Bruechle, NO, Drenth, JPH, Pelletier, L, Tapia-Páez, I, Lifton, RP, Giles, R, Kere, J & Hildebrandt, F 2015, 'DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling', American Journal of Human Genetics, vol. 96, no. 1, pp. 81-92. https://doi.org/10.1016/j.ajhg.2014.12.002

TY - JOUR

T1 - DCDC2 mutations cause a renal-hepatic ciliopathy by disrupting Wnt signaling

AU - Schueler, Markus

AU - Braun, Daniela A

AU - Chandrasekar, Gayathri

AU - Gee, Heon Yung

AU - Klasson, Timothy D.

AU - Halbritter, Jan

AU - Bieder, Andrea

AU - Porath, Jonathan D

AU - Airik, Rannar

AU - Zhou, Weibin

AU - LoTurco, Joseph J

AU - Che, Alicia

AU - Otto, Edgar A

AU - Böckenhauer, Detlef

AU - Sebire, Neil J

AU - Honzik, Tomas

AU - Harris, Peter C

AU - Koon, Sarah J

AU - Gunay-Aygun, Meral

AU - Saunier, Sophie

AU - Zerres, Klaus

AU - Bruechle, Nadina Ortiz

AU - Drenth, Joost P H

AU - Pelletier, Laurence

AU - Tapia-Páez, Isabel

AU - Lifton, Richard P

AU - Giles, R

AU - Kere, Juha

AU - Hildebrandt, Friedhelm

PY - 2015/1/8

Y1 - 2015/1/8

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Animals

KW - Cilia

KW - Computational Biology

KW - Exons

KW - HEK293 Cells

KW - Humans

KW - Kidney

KW - Kidney Diseases, Cystic

KW - Mice

KW - Microscopy, Electron, Transmission

KW - Microtubule-Associated Proteins

KW - Mutation

KW - NIH 3T3 Cells

KW - Phenotype

KW - Phosphoproteins

KW - Wnt Signaling Pathway

KW - Zebrafish

KW - beta Catenin

U2 - 10.1016/j.ajhg.2014.12.002

DO - 10.1016/j.ajhg.2014.12.002

M3 - Article

C2 - 25557784

SN - 0002-9297

VL - 96

SP - 81

EP - 92

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

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

Abstract

Keywords

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