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

Department of Pharmacology

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

70 Citations (Scopus)

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 - 2015 Jan 8

Bibliographical note

Funding Information:
We are grateful to families and study individuals for their contribution. We would like to thank Milan Elleder and Helena Hůlkova (Institute for Inherited Metabolic Disorders) for histological preparation of liver biopsy specimen. We thank the zebrafish core facility, Karolinska Institutet for providing zebrafish embryos. We thank Kjell Hultenby, Eva Blomen, and Sally Cheung for technical support. We thank the Live Cell Imaging unit/Nikon Center of Excellence, Department of Biosciences and Nutrition, Karolinska Institutet for their support. This research was supported by grants from the National Institutes of Health to F.H. (DK1069274, DK1068306, DK064614), to P.C.H. (DK090728, DK059597), to R.A. (DK099434), and by the CIHR to L.P. (MOP130507). H.Y.G. is supported by the NephCure Foundation and by the ASN Foundation for Kidney Research. T.H. was supported by General University Hospital program RVO-VFN 64165/2012. This work was in part supported by grants to J.K. from Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Centre for Biosciences, the Centre for Innovative Medicine, and Jonasson donation to the School of Technology and Health, Kungliga Tekniska Högskolan, Swedish Brain Foundation (Hjärnfonden) and Swedish Brain Foundations postdoc fellowship award to G.C., from the European Union Framework Programmes 241955 “SYSCILIA” and 305608 “EURenOmics” as well as the Dutch Kidney Foundation grants CP11.18 “KOUNCIL”/13A3D103 to R.H.G., and from the Deutsche Forschungs–gemeinschaft to K.Z. (ZE 205/14-1). F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and the Warren E. Grupe Professor.

Publisher Copyright:
© 2015 The American Society of Human Genetics.

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajhg.2014.12.002

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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

@article{e02b8c8ea978449a8abb85e1e9e93011,

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",

note = "Funding Information: We are grateful to families and study individuals for their contribution. We would like to thank Milan Elleder and Helena Hůlkova (Institute for Inherited Metabolic Disorders) for histological preparation of liver biopsy specimen. We thank the zebrafish core facility, Karolinska Institutet for providing zebrafish embryos. We thank Kjell Hultenby, Eva Blomen, and Sally Cheung for technical support. We thank the Live Cell Imaging unit/Nikon Center of Excellence, Department of Biosciences and Nutrition, Karolinska Institutet for their support. This research was supported by grants from the National Institutes of Health to F.H. (DK1069274, DK1068306, DK064614), to P.C.H. (DK090728, DK059597), to R.A. (DK099434), and by the CIHR to L.P. (MOP130507). H.Y.G. is supported by the NephCure Foundation and by the ASN Foundation for Kidney Research. T.H. was supported by General University Hospital program RVO-VFN 64165/2012. This work was in part supported by grants to J.K. from Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Centre for Biosciences, the Centre for Innovative Medicine, and Jonasson donation to the School of Technology and Health, Kungliga Tekniska H{\"o}gskolan, Swedish Brain Foundation (Hj{\"a}rnfonden) and Swedish Brain Foundations postdoc fellowship award to G.C., from the European Union Framework Programmes 241955 “SYSCILIA” and 305608 “EURenOmics” as well as the Dutch Kidney Foundation grants CP11.18 “KOUNCIL”/13A3D103 to R.H.G., and from the Deutsche Forschungs–gemeinschaft to K.Z. (ZE 205/14-1). F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and the Warren E. Grupe Professor. Publisher Copyright: {\textcopyright} 2015 The American Society of Human Genetics.",

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",

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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

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, Rachel H.

AU - Kere, Juha

AU - Hildebrandt, Friedhelm

N1 - Funding Information: We are grateful to families and study individuals for their contribution. We would like to thank Milan Elleder and Helena Hůlkova (Institute for Inherited Metabolic Disorders) for histological preparation of liver biopsy specimen. We thank the zebrafish core facility, Karolinska Institutet for providing zebrafish embryos. We thank Kjell Hultenby, Eva Blomen, and Sally Cheung for technical support. We thank the Live Cell Imaging unit/Nikon Center of Excellence, Department of Biosciences and Nutrition, Karolinska Institutet for their support. This research was supported by grants from the National Institutes of Health to F.H. (DK1069274, DK1068306, DK064614), to P.C.H. (DK090728, DK059597), to R.A. (DK099434), and by the CIHR to L.P. (MOP130507). H.Y.G. is supported by the NephCure Foundation and by the ASN Foundation for Kidney Research. T.H. was supported by General University Hospital program RVO-VFN 64165/2012. This work was in part supported by grants to J.K. from Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Centre for Biosciences, the Centre for Innovative Medicine, and Jonasson donation to the School of Technology and Health, Kungliga Tekniska Högskolan, Swedish Brain Foundation (Hjärnfonden) and Swedish Brain Foundations postdoc fellowship award to G.C., from the European Union Framework Programmes 241955 “SYSCILIA” and 305608 “EURenOmics” as well as the Dutch Kidney Foundation grants CP11.18 “KOUNCIL”/13A3D103 to R.H.G., and from the Deutsche Forschungs–gemeinschaft to K.Z. (ZE 205/14-1). F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist, and the Warren E. Grupe Professor. Publisher Copyright: © 2015 The American Society of Human Genetics.

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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DO - 10.1016/j.ajhg.2014.12.002

M3 - Article

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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

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