Loss of an extensive ciliary connectome induces proteostasis and cell fate switching in a severe motile ciliopathy
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ABSTRACT:
PROVIDER: PRJNA1149046 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30276301_1.fastq.gz | Fastqsanger.gz | |||
| SRR30276301_2.fastq.gz | Fastqsanger.gz | |||
| SRR30276302_1.fastq.gz | Fastqsanger.gz | |||
| SRR30276302_2.fastq.gz | Fastqsanger.gz |
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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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Project description:Oral-facial-digital syndromes (OFD) are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. To date, mutations in 12 ciliary-related genes have been identified to cause several OFD types suggesting OFDs constitute a subgroup of developmental ciliopathies. Through homozygosity mapping and exome sequencing performed on two families with variable OFD type 2, we identified distinct germline mutations in INTS13, a subunit of the Integrator Complex. This 14-component complex associates with RNAPII and can cleave nascent RNA to modulate gene expression. We determined that INTS13 utilizes a discrete domain within its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germline INTS13 mutations. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Accordingly, its knockdown in Xenopus embryos lead to motile cilia anomalies. Altogether, we show that mutations in INTS13 cause an autosomal recessive ciliopathy, which reveal key interactions within Integrator components.
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Project description:Tubulin, one of the most abundant cytoskeletal building blocks, exhibits extensive isotype diversity in humans. Displaying high similarity, whether these distinct isotypes form cell-type and context specific microtubule structures is poorly understood. Studying a cohort of 11 patients with the motile ciliopathy primary ciliary dyskinesia as well as mouse mutants, we report mutations in the TUBB4B isotype specifically perturb centriole and cilium biogenesis. We demonstrate that distinct TUBB4B mutations differentially affect microtubule dynamics and cilia formation in a dominant negative manner. Finally, structure-function studies reveal that different TUBB4B mutations disrupt distinct tubulin interfaces allowing clear stratification of patients into three classes of ciliopathic disease. These findings illustrate that specific tubulin isotypes have unique and non-redundant subcellular functions and establishes the missing link between human tubulinopathies and ciliopathies.
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Project description:Dysfunction of motile cilia can impair mucociliary clearance in the airway and result in primary ciliary dyskinesia (PCD), a pediatric syndrome characterized by chronic respiratory infection and bronchiectasis, as well as infertility, laterality defects, and occasionally hydrocephalus due to defects in cilia in other organ systems. We have previously shown that mutations in genes encoding components of the ciliary central pair apparatus (CPA) perturb ciliary motility and result in PCD in mouse models. However, little is known about how epithelial cell types in the ciliary microenvironment of the upper airway respond to defects in ciliary motility and mucociliary clearance. In this study, we have used a single-cell RNA sequencing (scRNA-seq) approach to investigate the effects of ciliary dysfunction on the tracheal epithelial cells from mouse models with mutations in CPA genes Cfap221 (also known as Pcdp1), Cfap54, and Spef2. Expected cell types were identified in the tracheal epithelial samples, including basal cells, suprabasal cells, secretory cells, deuterosomal cells, ciliated cells, tuft cells, ionocytes, and neuroendocrine cells, as well as an unidentified cell type that does not express markers of typical airway cells. The deuterosomal cells were found to exist in two states that differ largely in expression of genes involved in differentiation into the ciliated cell type. Differentially expressed genes (DEGs) were identified for each cell type, and functional enrichment analysis revealed a variety of important cellular functions altered in mutant cells. Overlapping DEGs shed light on general cellular responses to cilia dysfunction, while unique DEGs indicate that some responses may be specific to the individual mutation and ciliary defect. These analyses uncover new information about cellular responses to mucociliary clearance defects in the airway and pathogenesis of PCD.
2024-11-14 | GSE254100 | GEO
Project description:PurposeThe clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis.MethodsClinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants.ResultsIn this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments.ConclusionOur data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.
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