RRC ID 59955
Author Frikstad KM, 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.
Title A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling.
Journal Cell Rep
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.
Volume 28(7)
Pages 1907-1922.e6
Published 2019-8-13
DOI 10.1016/j.celrep.2019.07.025
PII S2211-1247(19)30922-2
PMID 31412255
PMC PMC6702141
MeSH Animals Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Cells, Cultured Cilia / physiology* Ciliopathies / metabolism Ciliopathies / pathology* Hedgehog Proteins / genetics Hedgehog Proteins / metabolism* Humans Microtubule-Associated Proteins / genetics Microtubule-Associated Proteins / metabolism* Mutation Retinal Pigment Epithelium / cytology Retinal Pigment Epithelium / metabolism* Signal Transduction Zebrafish / genetics Zebrafish / growth & development Zebrafish / metabolism Zebrafish Proteins / genetics Zebrafish Proteins / metabolism*
IF 7.815
Times Cited 3
Zebrafish Tg(CM-isl1:GFP)rw0