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Loss of an extensive ciliary connectome induces proteostasis and cell fate switching in a severe motile ciliopathy

ABSTRACT: CCDC39 is a motile cilia protein associated with primary ciliary dyskinesia. We used single cell RNA sequencing (scRNA-seq) to analyze the changes in cells types and gene expression profile of subjects with variants in CCDC39 compared to healthy individuals

ORGANISM(S): Homo sapiens

PROVIDER: GSE275070 | GEO | 2025/03/24

REPOSITORIES: GEO

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Loss of an extensive ciliary connectome induces proteostasis and cell fate switching in a severe motile ciliopathy.

Project description:Motile cilia have essential cellular functions in development, reproduction, and homeostasis. Genetic causes for motile ciliopathies have been identified, but the consequences on cellular functions beyond impaired motility remain unknown. Variants in CCDC39 and CCDC40 cause severe disease not explained by loss of motility. Using human cells with pathological variants in these genes, Chlamydomonas genetics, cryo-electron microscopy, single cell RNA transcriptomics, and proteomics, we identified perturbations in multiple cilia-independent pathways. Absence of the axonemal CCDC39/CCDC40 heterodimer results in loss of a connectome of over 90 proteins. The undocked connectome activates cell quality control pathways, switches multiciliated cell fate, impairs microtubule architecture, and creates a defective periciliary barrier. Both cilia-dependent and independent defects are likely responsible for the disease severity. Our findings provide a foundation for reconsidering the broad cellular impact of pathologic variants in ciliopathies and suggest new directions for therapies.

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Loss of an extensive ciliary connectome induces proteostasis and cell fate switching in a severe motile ciliopathy

Project description:Loss of an extensive ciliary connectome induces proteostasis and cell fate switching in a severe motile ciliopathy

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The Ciliary GTPase ARL13B maintains Ductule Physiology through the Primary and Motile Cilia in Male Reproduction

Project description:ARL13B is a small regulatory GTPase that controls ciliary membrane composition in both motile cilia and non-motile primary cilia. In this study, we investigated the role of ARL13B in the efferent ductules, tubules of the male reproductive tract essential to male fertility in which primary and motile cilia co-exist. We used a genetically engineered mouse model to deleteArl13bin efferent ductule epithelial cells, resulting in compromised primary and motile cilia architecture and functions. This deletion led to disturbances in reabsorptive/secretory processes and triggered an inflammatory response. The observed male reproductive phenotype showed significant variability linked to partial infertility, highlighting the importance of ARL13B in maintaining a proper physiological balance in these small ducts. These results emphasize the dual role of both motile and primary cilia functions in regulating efferent duct homeostasis, offering deeper insights into how cilia related diseases affect the male reproductive system.

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Genome-wide gene expression analysis in primary ciliary dyskinesia patients

Project description:We performed whole genome gene expression profiling in bronchial biopsies from PCD patients. We used the Quality Threshold clustering algorithm to identify groups of genes that revealed highly correlated RNA expression patterns in the biopsies. The largest cluster contained 372 genes and was significantly enriched for genes related to cilia. The database and literature search showed that 16250 genes in this cluster were known cilia genes, strongly indicating that the remaining 21022 genes were likely to be new cilia genes. The tissue expression pattern of the 210 new cilia genes and the 162 known genes was consistent with the presence of motile cilia in a given tissue. Analysis of the upstream promotor sequences revealed evidence for RFX transcription factors binding site motif in both subgroups. Total RNA obtained from 6 primary ciliary dyskinesia patients and 9 control individuals

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Cellular responses in the airway ciliary microenvironment from mouse models of primary ciliary dyskinesia with central pair apparatus defects

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Strain-specific differences in brain gene expression in a hydrocephalic mouse model with motile cilia dysfunction

Project description:Analysis of strain-specific differences in gene expression in brains from a hydrocephalic mouse model of primary ciliary dyskinesia. The results identify genes that are differentially expressed between C57BL6/J and 129S6/SvEvTac brains. These genes encode proteins that function in a variety of cellular processes and include some that are relevant to hydrocephalus and cilia function, providing insight into the mechanisms underlying susceptibility to hydrocephalus.

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Project description:Cilia are organelles specialized for movement and signaling. To infer when during animal evolution signaling pathways became associated with cilia, we characterized the proteomes of cilia from three organisms: sea urchins, sea anemones and choanoflagellates. From these ciliomes, we identified 437 high confidence ciliary candidate proteins conserved in mammals, including known regulators of Hh, GPCR and TRP channel signaling. The phylogenetic profiles of their ciliary association indicate that the Hh and GPCR pathways were linked to cilia before the origin of bilateria and TRP channels before the origin of animals. We demonstrated that some of the candidates not previously implicated in ciliary biology localized to cilia and further investigated ENKUR, a TRP channel-interacting protein that we identified in the cilia of all three organisms. In animals, ENKUR is expressed by cells with motile cilia, ENKUR localizes to cilia in diverse organisms and, in both Xenopus laevis and mice, ENKUR is required for patterning the left/right axis. Moreover, mutation of ENKUR causes situs inversus in humans. Thus, proteomic profiling of cilia from diverse eukaryotes defines a conserved ciliary proteome, reveals ancient connections to Hh, GPCR and TRP channel signaling, and uncovers a novel ciliary protein that controls vertebrate development and human disease.

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Project description:The Ciliary GTPase ARL13B maintains Ductule Physiology through the Primary and Motile Cilia in Male Reproduction

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