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

Lookup NU author(s): Dr Elisa MolinariORCiD, Dr Simon RamsbottomORCiD, Professor John SayerORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2019 The Authors. 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.

Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2019

Volume: 28

Issue: 7

Pages: 1907-1922

Print publication date: 13/08/2019

Online publication date: 13/08/2019

Acceptance date: 10/07/2019

Date deposited: 19/08/2019

ISSN (print): 2211-1247

Publisher: Elsevier BV


DOI: 10.1016/j.celrep.2019.07.025


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