A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling

Kari-Anne M. Frikstad; Elisa Molinari; Marianne Thoresen; Simon A. Ramsbottom; Frances Hughes; Stef J. F. Letteboer; Sania Gilani; Kay O. Schink; Trond Stokke; Stefan Geimer; Lotte Bang Pedersen; Rachel H. Giles; Anna Akhmanova; Ronald Roepman; John A. Sayer; Sebastian Patzke

doi:10.1016/j.celrep.2019.07.025

A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling

Kari-Anne M. Frikstad, Elisa Molinari, Marianne Thoresen, Simon A. Ramsbottom, Frances Hughes, Stef J. F. Letteboer, Sania Gilani, Kay O. Schink, Trond Stokke, Stefan Geimer, Lotte Bang Pedersen, Rachel H. Giles, Anna Akhmanova, Ronald Roepman, John A. Sayer, Sebastian Patzke

Cell Biology and Physiology

7 Citations (Scopus)

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Abstract

CEP104 is an evolutionarily conserved centrosomal and ciliary tip protein. CEP104 loss-of-function mutations are reported in patients with Joubert syndrome, but their function in the etiology of ciliopathies is poorly understood. Here, we show that cep104 silencing in zebrafish causes cilia-related manifestations: shortened cilia in Kupffer's vesicle, heart laterality, and cranial nerve development defects. We show that another Joubert syndrome-associated cilia tip protein, CSPP1, interacts with CEP104 at microtubules for the regulation of axoneme length. We demonstrate in human telomerase reverse transcriptase-immortalized retinal pigmented epithelium (hTERT-RPE1) cells that ciliary translocation of Smoothened in response to Hedgehog pathway stimulation is both CEP104 and CSPP1 dependent. However, CEP104 is not required for the ciliary recruitment of CSPP1, indicating that an intra-ciliary CEP104-CSPP1 complex controls axoneme length and Hedgehog signaling competence. Our in vivo and in vitro analyses of CEP104 define its interaction with CSPP1 as a requirement for the formation of Hedgehog signaling-competent cilia, defects that underlie Joubert syndrome. Deleterious mutations in CEP104 or CSPP1 cause Joubert syndrome, a ciliopathy causing an underdeveloped mid- and/or hindbrain. Frikstad et al. show that loss of cep104 in zebrafish leads to defective brain development and that CEP104 interacts with CSPP1 at the tip of the primary cilium to regulate axoneme length and Hedgehog signaling competence.

Original language	English
Journal	Cell Reports
Volume	28
Issue number	7
Pages (from-to)	1907-1922, e1-e6
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2019.07.025
Publication status	Published - 13 Aug 2019

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A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog SignalingFinal published version, 5.38 MBLicence: CC BY-NC-ND

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Frikstad, K.-A. M., Molinari, E., Thoresen, M., Ramsbottom, S. A., Hughes, F., Letteboer, S. J. F., Gilani, S., Schink, K. O., Stokke, T., Geimer, S., Pedersen, L. B., Giles, R. H., Akhmanova, A., Roepman, R., Sayer, J. A., & Patzke, S. (2019). A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling. Cell Reports, 28(7), 1907-1922, e1-e6. https://doi.org/10.1016/j.celrep.2019.07.025

Frikstad, K-AM, Molinari, E, Thoresen, M, Ramsbottom, SA, Hughes, F, Letteboer, SJF, Gilani, S, Schink, KO, Stokke, T, Geimer, S, Pedersen, LB, Giles, RH, Akhmanova, A, Roepman, R, Sayer, JA & Patzke, S 2019, 'A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling', Cell Reports, vol. 28, no. 7, pp. 1907-1922, e1-e6. https://doi.org/10.1016/j.celrep.2019.07.025

@article{aa08e4ee2f8c4197877b6f7930436a33,

title = "A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling",

abstract = "CEP104 is an evolutionarily conserved centrosomal and ciliary tip protein. CEP104 loss-of-function mutations are reported in patients with Joubert syndrome, but their function in the etiology of ciliopathies is poorly understood. Here, we show that cep104 silencing in zebrafish causes cilia-related manifestations: shortened cilia in Kupffer's vesicle, heart laterality, and cranial nerve development defects. We show that another Joubert syndrome-associated cilia tip protein, CSPP1, interacts with CEP104 at microtubules for the regulation of axoneme length. We demonstrate in human telomerase reverse transcriptase-immortalized retinal pigmented epithelium (hTERT-RPE1) cells that ciliary translocation of Smoothened in response to Hedgehog pathway stimulation is both CEP104 and CSPP1 dependent. However, CEP104 is not required for the ciliary recruitment of CSPP1, indicating that an intra-ciliary CEP104-CSPP1 complex controls axoneme length and Hedgehog signaling competence. Our in vivo and in vitro analyses of CEP104 define its interaction with CSPP1 as a requirement for the formation of Hedgehog signaling-competent cilia, defects that underlie Joubert syndrome. Deleterious mutations in CEP104 or CSPP1 cause Joubert syndrome, a ciliopathy causing an underdeveloped mid- and/or hindbrain. Frikstad et al. show that loss of cep104 in zebrafish leads to defective brain development and that CEP104 interacts with CSPP1 at the tip of the primary cilium to regulate axoneme length and Hedgehog signaling competence.",

author = "Frikstad, {Kari-Anne M.} and Elisa Molinari and Marianne Thoresen and Ramsbottom, {Simon A.} and Frances Hughes and Letteboer, {Stef J. F.} and Sania Gilani and Schink, {Kay O.} and Trond Stokke and Stefan Geimer and Pedersen, {Lotte Bang} and Giles, {Rachel H.} and Anna Akhmanova and Ronald Roepman and Sayer, {John A.} and Sebastian Patzke",

year = "2019",

month = aug,

day = "13",

doi = "10.1016/j.celrep.2019.07.025",

language = "English",

volume = "28",

pages = "1907--1922, e1--e6",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "7",

}

TY - JOUR

T1 - A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling

AU - Frikstad, Kari-Anne M.

AU - Molinari, Elisa

AU - Thoresen, Marianne

AU - Ramsbottom, Simon A.

AU - Hughes, Frances

AU - Letteboer, Stef J. F.

AU - Gilani, Sania

AU - Schink, Kay O.

AU - Stokke, Trond

AU - Geimer, Stefan

AU - Pedersen, Lotte Bang

AU - Giles, Rachel H.

AU - Akhmanova, Anna

AU - Roepman, Ronald

AU - Sayer, John A.

AU - Patzke, Sebastian

PY - 2019/8/13

Y1 - 2019/8/13

N2 - CEP104 is an evolutionarily conserved centrosomal and ciliary tip protein. CEP104 loss-of-function mutations are reported in patients with Joubert syndrome, but their function in the etiology of ciliopathies is poorly understood. Here, we show that cep104 silencing in zebrafish causes cilia-related manifestations: shortened cilia in Kupffer's vesicle, heart laterality, and cranial nerve development defects. We show that another Joubert syndrome-associated cilia tip protein, CSPP1, interacts with CEP104 at microtubules for the regulation of axoneme length. We demonstrate in human telomerase reverse transcriptase-immortalized retinal pigmented epithelium (hTERT-RPE1) cells that ciliary translocation of Smoothened in response to Hedgehog pathway stimulation is both CEP104 and CSPP1 dependent. However, CEP104 is not required for the ciliary recruitment of CSPP1, indicating that an intra-ciliary CEP104-CSPP1 complex controls axoneme length and Hedgehog signaling competence. Our in vivo and in vitro analyses of CEP104 define its interaction with CSPP1 as a requirement for the formation of Hedgehog signaling-competent cilia, defects that underlie Joubert syndrome. Deleterious mutations in CEP104 or CSPP1 cause Joubert syndrome, a ciliopathy causing an underdeveloped mid- and/or hindbrain. Frikstad et al. show that loss of cep104 in zebrafish leads to defective brain development and that CEP104 interacts with CSPP1 at the tip of the primary cilium to regulate axoneme length and Hedgehog signaling competence.

AB - CEP104 is an evolutionarily conserved centrosomal and ciliary tip protein. CEP104 loss-of-function mutations are reported in patients with Joubert syndrome, but their function in the etiology of ciliopathies is poorly understood. Here, we show that cep104 silencing in zebrafish causes cilia-related manifestations: shortened cilia in Kupffer's vesicle, heart laterality, and cranial nerve development defects. We show that another Joubert syndrome-associated cilia tip protein, CSPP1, interacts with CEP104 at microtubules for the regulation of axoneme length. We demonstrate in human telomerase reverse transcriptase-immortalized retinal pigmented epithelium (hTERT-RPE1) cells that ciliary translocation of Smoothened in response to Hedgehog pathway stimulation is both CEP104 and CSPP1 dependent. However, CEP104 is not required for the ciliary recruitment of CSPP1, indicating that an intra-ciliary CEP104-CSPP1 complex controls axoneme length and Hedgehog signaling competence. Our in vivo and in vitro analyses of CEP104 define its interaction with CSPP1 as a requirement for the formation of Hedgehog signaling-competent cilia, defects that underlie Joubert syndrome. Deleterious mutations in CEP104 or CSPP1 cause Joubert syndrome, a ciliopathy causing an underdeveloped mid- and/or hindbrain. Frikstad et al. show that loss of cep104 in zebrafish leads to defective brain development and that CEP104 interacts with CSPP1 at the tip of the primary cilium to regulate axoneme length and Hedgehog signaling competence.

U2 - 10.1016/j.celrep.2019.07.025

DO - 10.1016/j.celrep.2019.07.025

M3 - Journal article

C2 - 31412255

SN - 2211-1247

VL - 28

SP - 1907-1922, e1-e6

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -

A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling

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