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

被引：29

作者：

Frikstad, Kari-Anne M. ^{[1
]}

Molinari, Elisa ^{[2
]}

Thoresen, Marianne ^{[1
]}

Ramsbottom, Simon A. ^{[2
]}

Hughes, Frances ^{[2
]}

Letteboer, Stef J. F. ^{[3
,4
]}

Gilani, Sania ^{[1
]}

Schink, Kay O. ^{[5
]}

Stokke, Trond ^{[1
]}

Geimer, Stefan ^{[6
]}

Pedersen, Lotte B. ^{[7
]}

Giles, Rachel H. ^{[8
]}

Akhmanova, Anna ^{[9
]}

Roepman, Ronald ^{[3
,4
]}

Sayer, John A. ^{[2
,10
,11
]}

Patzke, Sebastian ^{[1
]}

机构：

[1] OUH Norwegian Radium Hosp, Inst Canc Res, Dept Radiat Biol, Oslo, Norway

[2] Newcastle Univ, Inst Med Genet, Int Ctr Life, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[3] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Med Ctr, Nijmegen, Netherlands

[5] OUH Norwegian Radium Hosp, Inst Canc Res, Dept Mol Cell Biol, Oslo, Norway

[6] Univ Bayreuth, Cell Biol Electron Microscopy, Bayreuth, Germany

[7] Univ Copenhagen, Dept Biol, Copenhagen, Denmark

[8] Univ Med Ctr Utrecht, Dept Hypertens & Nephrol, Regenerat Med Ctr Utrecht, Utrecht, Netherlands

[9] Univ Utrecht, Dept Cell Biol, Fac Sci, Utrecht, Netherlands

[10] Newcastle Upon Tyne NHS Fdn Trust, Freeman Rd, Newcastle, NSW NE7 7DN, Australia

[11] Biomed Res Ctr, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England

来源：

CELL REPORTS | 2019年 / 28卷 / 07期

基金：

英国医学研究理事会;

关键词：

JOUBERT SYNDROME; TRANSITION ZONE; CEREBELLAR DEVELOPMENT; CENTROSOMAL PROTEIN; MUTATIONS; REVEALS; INPP5E; TRAFFICKING; TRANSPORT; DEFECTS;

D O I：

10.1016/j.celrep.2019.07.025

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1907 / +

页数：22