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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.

SUBMITTER: Frikstad KM

PROVIDER: S-EPMC6702141 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Frikstad Kari-Anne M KM Molinari Elisa E Thoresen Marianne M Ramsbottom Simon A SA Hughes Frances F Letteboer Stef J F SJF Gilani Sania S Schink Kay O KO Stokke Trond T Geimer Stefan S Pedersen Lotte B LB Giles Rachel H RH Akhmanova Anna A Roepman Ronald R Sayer John A JA Patzke Sebastian S

Cell reports 20190801 7

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 ...[more]

PMID: 31412255

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Project description:Background:Primary cilia are small non-motile microtubule and cell membrane protrusions expressed on most vertebrate cells, including cortical and hippocampal neurons. These small organelles serve as sensory structures sampling the extracellular environment and reprogramming the transcriptional machinery in response to environmental change. Primary cilia are decorated with a variety of receptor proteins and are necessary for specific signaling cascades such as the Sonic hedgehog (Shh) pathway. Disrupting cilia structure or function results in a spectrum of diseases collectively referred to as ciliopathies. Common to human ciliopathies is cognitive impairment, a symptom also observed in Alzheimer's disease (AD). One hallmark of AD is accumulation of senile plaques composed of neurotoxic Amyloid-? (A?) peptide. The A? peptide is generated by the proteolytic cleavage of the amyloid precursor protein (APP). We set out to determine if A? affects primary cilia structure and the Shh signaling cascade. Methods:We utilized in vitro cell-based assays in combination with fluorescent confocal microscopy to address our study goals. Shh signaling and cilia structure was studied using two different cell lines, mouse NIH3T3 and human HeLa cells. To investigate how A? levels affect Shh signaling and cilia structure in these cells, we utilized naturally secreted A? as well as synthetic A?. Effects on Shh signaling were assessed by luciferase activity while cilia structure was analyzed by fluorescent microscopy. Results:Here, we report that APP localizes to primary cilia and A? treatment results in distorted primary cilia structure. In addition, we demonstrate that A? treatment interrupts canonical Shh signal transduction. Conclusions:Overall, our study illustrates that A? can alter primary cilia structure suggesting that elevated A? levels, like those observed in AD patients, could have similar effects on neuronal primary cilia in the brain. Additionally, our study suggests that A? impairs the Shh signaling pathway. Together our findings shed light on two novel targets for future AD therapeutics.

Dataset Information

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

Publications

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

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