Schizophrenia-related microdeletion causes progressive brain ventricle enlargement through microRNA-dependent deceleration of motile cilia beating
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ABSTRACT:
PROVIDER: PRJNA509221 | ENA |
REPOSITORIES: ENA
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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.
2026-01-06 | GSE301791 | 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: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: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
2025-03-24 | GSE275070 | 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:Adipose tissue-derived stromal vascular fraction (Ad-SVF) contains stem cells and rarely transdifferentiate into spontaneously beating cardiomyocyte-like cells (beating CMs). However, the factors that regulate the differentiation of Ad-SVF into the cardiac lineage is unknown. We developed a simple culture protocol under which the adult murine inguinal Ad-SVF reproducibly transdifferentiates into beating CMs without induction. We used microarray analyses to evaluate the global gene expressions of the beating CMs and investigated the mechanism underlying the transdifferentiation of SVF cells into CMs.
2021-01-21 | GSE154301 | GEO
Project description:Organs from nonheart-beating donors are attractive for use in cell therapy. Understanding the nature of molecular perturbations following reperfusion/reoxygenation would be highly significant for nonheart-beating donor cells. Nonheart-beating donor rats hepatocytes were studied for global gene expression with Affymetrix microarraays.
2018-11-06 | GSE122179 | GEO
Project description:Adenosine N6-methylation (m6A) is one of the most pervasive mRNA modifications, and yet the physiological significance of m6A removal (demethylation) remains elusive. Here we report the m6A demethylase FTO functions as a conserved regulator of motile ciliogenesis. Mechanistically, FTO demethylates and thereby stabilizes the mRNA encoding the master ciliary transcription factor FOXJ1. Depletion of Fto in Xenopus laevis embryos caused widespread motile cilia defects, and Foxj1 was identified as one of the major phenocritical targets. In primary human airway epithelium, FTO depletion also led to FOXJ1 mRNA destabilization and a severe loss of ciliated cells with an increase of neighboring goblet cells. Consistently, Fto knockout mice showed strong asthma-like phenotypes upon allergen challenge owing to defective ciliated cells in the airway epithelium. Altogether, our study reveals a conserved role of the FTO-FOXJ1 axis in embryonic and homeostatic motile ciliogenesis.
2021-02-20 | GSE167139 | 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