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Schizophrenia-related microdeletion causes progressive brain ventricle enlargement through microRNA-dependent deceleration of motile cilia beating

ABSTRACT: Schizophrenia-related microdeletion causes progressive brain ventricle enlargement through microRNA-dependent deceleration of motile cilia beating

PROVIDER: PRJNA509221 | ENA |

REPOSITORIES: ENA

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Schizophrenia-related microdeletion causes progressive brain ventricle enlargement through microRNA-dependent deceleration of motile cilia beating

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

Quantitative label-free proteomic analysis of Wdr47+/+ and Wdr47-/- mouse motile cilia

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 | iProX

Effect of FoxJ1 on expression of cilia genes

Project description:Analysis of epithelial explants injected with the intracellular domain of Notch (ICD) to block the formation of multi-ciliate cells, either alone or along with FoxJ1. FoxJ1 misexpression leads to the induction fo ectopic cilia in Xenopus laevis epithelia. Results show which genes are affected by FoxJ1 during the induction of ectopic cilia. Ciliated cells that produce a leftward fluid flow have been proposed to mediate left-right patterning in many vertebrate embryos. These cilia combine features of primary sensory and motile cilia, but how such cilia are specified is unknown. We address this issue by analyzing the Xenopus and Zebrafish homologs of FoxJ1, a forkhead transcription factor necessary for ciliogenesis in multi-ciliate cells of the mouse. We show that the cilia that underlie left-right patterning on the Xenopus gastrocoel roof plate (GRP) and Zebrafish Kupffer’s vesicle (KV) are severely shortened or fail to form in FoxJ1 morphants. We also show that misexpressing XFoxJ1 is sufficient to induce ectopic GRP-like cilia formation in frog embryos. Microarray analysis indicates that XFoxJ1 induces the formation of cilia by upregulating the expression of motile cilia genes. These results indicate that FoxJ1 is a critical determinant in specifying cilia used in left-right patterning. Keywords: Cilia Induction

2008-09-15 | GSE12613 | GEO

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

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

| PRJNA450525 | ENA

Smoking is Associated with Shortened Airway Cilia

Project description:Background: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting cilia length must exceed the 6 -7 μm airway surface fluid depth to generate force in the mucus layer, we hypothesized cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers. Methodology/Principal Findings: Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced 15% compared to nonsmokers (p<0.05). In 47 air-dried samples of airway epithelial cells, smoker cilia length was reduced 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 17 samples, smoker cilia length was reduced 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05). Conclusions/significance: Models predict that a reduction in cilia length would reduce mucociliary clearance, suggesting that smoking-associated shorter airway epithelial cilia plays a significant role in the pathogenesis of smoking-induced lung disease.

2012-12-13 | E-GEOD-16696 | biostudies-arrayexpress

Proteomics of mouse ependymal cilia

Project description:Two 75-cm2 flasks of ependymal cells derived from ten E18.5 C57BL/6J mouse embryos at the day 10 post serum starvation were harvested and motile cilia were collected for mass spectrometry analysis.

2021-10-18 | PXD029174 | iProX

Identification of the FTO-FOXJ1 axis as a conserved regulatory module of embryonic and homeostatic motile ciliogenesis

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

Motility gene expression in L. ruminis ATCC25644 vs L. ruminis ATCC27782 during motile and non-motile growth in MRS media

Project description:The genus Lactobacillus contains over 100 different species that were traditionally considered to be uniformly non-motile. However, at least twelve motile species are known to exist in the L. salivarius clade of this genus. Of these, Lactobacillus rumnis is the only motile species that is also autochthonous to the mammalian gastrointestinal tract. The genomes of two L. ruminis strains, ATCC25644 (human isolate, non-motile) and ATCC27782 (bovine isolate, motile) were sequenced and annotated to identify the genes responsible for flagellum biogenesis and chemotaxis in this species. Transcriptome analysis revealed that motility genes were transcribed at a significantly higher level in motile L. ruminis ATCC27782 than in non-motile ATCC25644 during the motile growth phase.

2012-07-10 | GSE31556 | GEO

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.

2018-09-06 | GSE113233 | GEO