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; Rachel H. 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, Rachel H. Giles, Juha Kere, Friedhelm Hildebrandt

Nephrology and Hypertension

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

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 (US)
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
State	Published - Jan 8 2015

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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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

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, RH, 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

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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.",

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 Giles, {Rachel H.} and Juha Kere and Friedhelm Hildebrandt",

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

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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, Rachel H.

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.

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SN - 0002-9297

VL - 96

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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

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