CFAP298 governs dynein arm protein homeostasis to ensure motile cilia function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE345015 | GEO | 2026/08/30
REPOSITORIES: GEO
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| GSE345015_all_counts.txt.gz | Txt |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
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.
2024-09-30 | GSE256400 | GEO
Project description:Assembly of the axonemal dynein motors that power ciliary motility occurs in the cytoplasm. Studies in a broad array of organisms have revealed that at least nineteen cytosolic factors are specifically required for this process. Recently, one of these factors (DNAAF3/PF22) was identified as an S-adenosylmethionine-dependent methyltransferase. Furthermore, examination of dyneins from the green alga Chlamydomonas found that axonemal dyneins are methylated at sub-stoichiometric levels on multiple sites including key Lys and Arg residues in several of the nucleotide binding domains and on the microtubule-binding region. Given the highly conserved nature of axonemal dyneins and their cytoplasmic assembly factors, one key question is whether methylation is exclusively present only in dyneins from the chlorophyte algae, or if these modifications occur more broadly throughout the motile ciliated eukaryotes. Here we take a phylo-proteomic approach and examine dynein methylation in a wide range of eukaryotic organisms bearing motile cilia. We find unambiguous evidence for methylation of axonemal dyneins in alveolates, chlorophytes, trypanosomes, and throughout most of the metazoa, including ctenophores, echinoderms, mollusks, ascidians, and vertebrates. Intriguingly, we were unable to identify a single instance of methylation on Drosophila sperm dynein even though dipterans express a Dnaaf3 ortholog, or in spermatozoids of the fern Ceratopteris which assembles inner arms but lacks both outer arm dyneins and DNAAF3. Thus, methylation is a post-translational feature of axonemal dyneins that has been broadly conserved in most eukaryotic groups suggesting the existence of a post-translational dynein code that variably modifies the function of these motors.
2025-02-20 | PXD055793 | Pride
Project description:Assembly of the axonemal dynein motors that power ciliary motility occurs in the cytoplasm. Studies in a broad array of organisms have revealed that at least nineteen cytosolic factors are specifically required for this process. Recently, one of these factors (DNAAF3/PF22) was identified as an S-adenosylmethionine-dependent methyltransferase. Furthermore, examination of dyneins from the green alga Chlamydomonas found that axonemal dyneins are methylated at sub-stoichiometric levels on multiple sites including key Lys and Arg residues in several of the nucleotide binding domains and on the microtubule-binding region. Given the highly conserved nature of axonemal dyneins and their cytoplasmic assembly factors, one key question is whether methylation is exclusively present only in dyneins from the chlorophyte algae, or if these modifications occur more broadly throughout the motile ciliated eukaryotes. Here we take a phylo-proteomic approach and examine dynein methylation in a wide range of eukaryotic organisms bearing motile cilia. We find unambiguous evidence for methylation of axonemal dyneins in alveolates, chlorophytes, trypanosomes, and throughout most of the metazoa, including ctenophores, echinoderms, mollusks, ascidians, and vertebrates. Intriguingly, we were unable to identify a single instance of methylation on Drosophila sperm dynein even though dipterans express a Dnaaf3 ortholog, or in spermatozoids of the fern Ceratopteris which assembles inner arms but lacks both outer arm dyneins and DNAAF3. Thus, methylation is a post-translational feature of axonemal dyneins that has been broadly conserved in most eukaryotic groups suggesting the existence of a post-translational dynein code that variably modifies the function of these motors.
2025-02-20 | PXD058873 | Pride
Project description:To clarify the role of Wdr92, and R2TP, in motile cilium formation, we explored its function in Drosophila. We show that Drosophila Wdr92 is a cytoplasmic protein exclusively expressed in motile ciliated cells and is required exclusively for ciliary/flagellar motility. The major effect of its mutation is loss of dynein arms from the axonemes of sensory neuron cilia and sperm flagella. We confirm that Drosophila Wdr92 interacts with R2TP and that R2TP depletion also impairs dynein arm formation. We provide proteomic evidence that Wdr92 is associated especially with heavy chain assembly and propose that it acts as a specificity factor to bring axonemal dynein clients to the R2TP/HSP90 complex. Thus, Wdr92 is a new dynein assembly factor and it strongly reinforces the critical role of HSP90 and co-chaperones in dynein assembly.
2018-04-25 | PXD006935 | Pride
Project description:Progressive ventricular enlargement is one of the most reproducible and recognizable structural abnormalities in schizophrenia, and is associated with more severe symptoms and poorer clinical outcome. The mechanisms of ventricular enlargement in schizophrenia is unknown. We identified that progressive ventricular enlargement is associated with deceleration of motile cilia beating in ependymal cells lining ventricular walls in murine models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). The cilia beating deficit is caused by an aberrant elevation of Drd1, which is highly enriched in the motile cilia. Haploinsufficiency of the microRNA-processing gene Dgcr8 is responsible for the Drd1 elevation in ependymal cells of 22q11DS mice, and is mediated by reduction of Drd1-targeting microRNAs miR-674-3p and miR-382-3p. Replenishing miR-674-3p or miR-382-3p in 22q11DS mice rescued the motile cilia beating abnormalities and normalized the ventricular size. Knockdown of these microRNA mimicked cilia beating and ventricular deficits. Ventricular enlargement was also caused by Crispr/cas9-mediated deletion of the Drd1 seed site for miR-674-3p/miR-382-3p. This suggests that Dgcr8-miR-674-3p/miR-382-3p-Drd1–dependent disruption of cilia motility in ependymal cells is a pathogenic event underlying schizophrenia-associated ventricular enlargement.
2019-12-07 | GSE123560 | GEO
Project description:Background: Multiple sclerosis is a neurodegenerative autoimmune disorder of the central nervous system (CNS) in which autoreactive immune cells migrate through a damaged blood brain barrier, resulting in focal demyelinating lesions of both the white and grey matter. Of increasing interest is the repeated observation that beyond focal lesions, there are also diffuse, surface-in gradients of pathology in MS, wherein damage is most severe directly adjacent to cerebrospinal fluid (CSF)-contacting surfaces, such as the subpial and periventricular areas. This observation suggests that toxic factors within MS CSF may be contributing to the emer-gence and/or evolution of surface-in gradients. Directly separating the CSF from the periventricular parenchyma are ependymal cells – a glial epithelium that expresses tufts of motile cilia which are critical for circulating CSF solutes and regulating local fluid flow. While damage to ependymal cilia has the potential to drastically modify CSF homeostasis and thus contribute to the damage of CSF exposed regions, these motile cellular structures have yet to be investigated in the context of MS. Methods: We first conducted single cell RNA sequencing of fresh human periventricular brain tissue containing ependymal cells from MS patients and non-MS disease controls. We subse-quently collected CSF from MS patients and exposed cultured rodent ependymal cells to this CSF in order to evaluate impact on ependymal ciliary function. To complement our direct eval-uation of cilia in the context of MS, we also confirmed whether cilia were altered in a classic animal model of MS, experimental autoimmune encephalomyelitis (EAE), and also designed a novel transgenic animal model to evaluate the cellular and behavioural effect(s) of adult ep-endymal ciliary disruption. Results: Single cell RNA sequencing analysis of human ependymal cells in MS demonstrated largescale dysregulation of ciliary genes; in situ stains of MS brain tissue confirmed a loss of ependymal cilia in MS compared to control. Exposure of ependymal cells to MS CSF led to transcriptional modification of ciliary gene expression and reduced ciliary beating frequency. Likewise, analysis of ependymal cells in EAE also demonstrated altered cilia gene expression. Conditional knockout of the critical cilia-associated gene Ccdc39 in ependymal cells led to transient ventricular enlargement, increased periventricular microglial density, and alterations in nesting behaviour. Conclusion: These data suggest that cilia are dysregulated in CNS autoimmunity. More im-portantly, however, they provide evidence to suggest that ependymal cilia disruption could play an active role in the development of periventricular pathology in MS, and can lead to behav-ioural deficits that may underlie aspects non-motor MS symptomatology.
2025-12-31 | GSE301585 | GEO
Project description:Background: Multiple sclerosis is a neurodegenerative autoimmune disorder of the central nervous system (CNS) in which autoreactive immune cells migrate through a damaged blood brain barrier, resulting in focal demyelinating lesions of both the white and grey matter. Of increasing interest is the repeated observation that beyond focal lesions, there are also diffuse, surface-in gradients of pathology in MS, wherein damage is most severe directly adjacent to cerebrospinal fluid (CSF)-contacting surfaces, such as the subpial and periventricular areas. This observation suggests that toxic factors within MS CSF may be contributing to the emer-gence and/or evolution of surface-in gradients. Directly separating the CSF from the periventricular parenchyma are ependymal cells – a glial epithelium that expresses tufts of motile cilia which are critical for circulating CSF solutes and regulating local fluid flow. While damage to ependymal cilia has the potential to drastically modify CSF homeostasis and thus contribute to the damage of CSF exposed regions, these motile cellular structures have yet to be investigated in the context of MS. Methods: We first conducted single cell RNA sequencing of fresh human periventricular brain tissue containing ependymal cells from MS patients and non-MS disease controls. We subse-quently collected CSF from MS patients and exposed cultured rodent ependymal cells to this CSF in order to evaluate impact on ependymal ciliary function. To complement our direct eval-uation of cilia in the context of MS, we also confirmed whether cilia were altered in a classic animal model of MS, experimental autoimmune encephalomyelitis (EAE), and also designed a novel transgenic animal model to evaluate the cellular and behavioural effect(s) of adult ep-endymal ciliary disruption. Results: Single cell RNA sequencing analysis of human ependymal cells in MS demonstrated largescale dysregulation of ciliary genes; in situ stains of MS brain tissue confirmed a loss of ependymal cilia in MS compared to control. Exposure of ependymal cells to MS CSF led to transcriptional modification of ciliary gene expression and reduced ciliary beating frequency. Likewise, analysis of ependymal cells in EAE also demonstrated altered cilia gene expression. Conditional knockout of the critical cilia-associated gene Ccdc39 in ependymal cells led to transient ventricular enlargement, increased periventricular microglial density, and alterations in nesting behaviour. Conclusion: These data suggest that cilia are dysregulated in CNS autoimmunity. More im-portantly, however, they provide evidence to suggest that ependymal cilia disruption could play an active role in the development of periventricular pathology in MS, and can lead to behav-ioural deficits that may underlie aspects non-motor MS symptomatology.
2026-01-06 | GSE301791 | GEO
Project description:The brain uses a specialized system to transport cerebrospinal fluid (CSF), consisting of interconnected ventricles lined by motile ciliated ependymal cells. These cells act jointly with CSF secretion and cardiac pressure gradients to regulate CSF dynamics. To date, the link between cilia-mediated CSF flow and brain function is poorly understood. Using zebrafish larvae as a model system, we identify that loss of ciliary motility does not alter progenitor proliferation, brain morphology, or spontaneous neural activity despite leading to an enlarged telencephalic ventricle. We observe altered neuronal responses to photic stimulations in the optic tectum and hindbrain and brain asymmetry defects in the habenula. Finally, we investigate astroglia since they contact CSF and regulate neuronal activity. Our analyses reveal a reduction in astroglial calcium signals during both spontaneous and light-evoked activity. Our findings highlight a role of motile cilia in regulating brain physiology through the modulation of neural and astroglial networks.
2024-11-22 | GSE254006 | GEO
Project description:Eukaryotic cilia and flagella are essential for cell motility and sensory functions. Their biogenesis and maintenance rely on the intraflagellar transport (IFT). Several cargo adapters have been identified to aid IFT cargo transport, but how ciliary cargos are discharged from IFT remains largely unknown. During our explorations of small GTPases ARL13 and ARL3 in Trypanosoma brucei, we found that ODA16, a known IFT cargo adapter found exclusively in motile cilia, is a specific effector of ARL3. To investigate how TbARL3A and TbARL3C regulate TbODA16, we performed proximity-dependent biotin identification (BioID) and mass spectrometry analyses for TbODA16 in the presence or absence of TbARL3A and TbARL3C.
2024-09-05 | PXD053760 | Pride
Project description:Two 75-cm2 flasks of ependymal cells derived from ten E18.5 Wdr47+/+ or Wdr47-/- embryos at the day 10 post serum starvation were harvested and motile cilia were purified for quantitative label-free proteomic analysis.
2021-09-07 | PXD028219 |