Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Schizophrenia-related microdeletion causes defective ciliary motility and brain ventricle enlargement via microRNA-dependent mechanisms in mice.

ABSTRACT: Progressive ventricular enlargement, a key feature of several neurologic and psychiatric diseases, is mediated by unknown mechanisms. Here, using murine models of 22q11-deletion syndrome (22q11DS), which is associated with schizophrenia in humans, we found progressive enlargement of lateral and third ventricles and deceleration of ciliary beating on ependymal cells lining the ventricular walls. The cilia-beating deficit observed in brain slices and in vivo is caused by elevated levels of dopamine receptors (Drd1), which are expressed in motile cilia. Haploinsufficiency of the microRNA-processing gene Dgcr8 results in Drd1 elevation, which is brought about by a reduction in Drd1-targeting microRNAs miR-382-3p and miR-674-3p. Replenishing either microRNA in 22q11DS mice normalizes ciliary beating and ventricular size. Knocking down the microRNAs or deleting their seed sites on Drd1 mimicked the cilia-beating and ventricular deficits. These results suggest that the Dgcr8-miR-382-3p/miR-674-3p-Drd1 mechanism contributes to deceleration of ciliary motility and age-dependent ventricular enlargement in 22q11DS.

SUBMITTER: Eom TY

PROVIDER: S-EPMC7021727 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

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

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

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

| PRJNA509221 | ENA

?3Na+/K+-ATPase deficiency causes brain ventricle dilation and abrupt embryonic motility in zebrafish.

Project description:Na(+)/K(+)-ATPases are transmembrane ion pumps that maintain ion gradients across the basolateral plasma membrane in all animal cells to facilitate essential biological functions. Mutations in the Na(+)/K(+)-ATPase ?3 subunit gene (ATP1A3) cause rapid-onset dystonia-parkinsonism, a rare movement disorder characterized by sudden onset of dystonic spasms and slow movements. In the brain, ATP1A3 is principally expressed in neurons. In zebrafish, the transcripts of the two ATP1A3 orthologs, Atp1a3a and Atp1a3b, show distinct expression in the brain. Surprisingly, targeted knockdown of either Atp1a3a or Atp1a3b leads to brain ventricle dilation, a likely consequence of ion imbalances across the plasma membrane that cause accumulation of cerebrospinal fluid in the ventricle. The brain ventricle dilation is accompanied by a depolarization of spinal Rohon-Beard neurons in Atp1a3a knockdown embryos, suggesting impaired neuronal excitability. This is further supported by Atp1a3a or Atp1a3b knockdown results where altered responses to tactile stimuli as well as abnormal motility were observed. Finally, proteomic analysis identified several protein candidates highlighting proteome changes associated with the knockdown of Atp1a3a or Atp1a3b. Our data thus strongly support the role of ?3Na(+)/K(+)-ATPase in zebrafish motility and brain development, associating for the first time the ?3Na(+)/K(+)-ATPase deficiency with brain ventricle dilation.

| S-EPMC3610961 | biostudies-literature

Pallidum and lateral ventricle volume enlargement in autism spectrum disorder.

Project description:Studies on structural brain abnormalities in individuals with autism spectrum disorders (ASD) have been of limited size and many findings have not been replicated. In the largest ASD brain morphology study to date, we compared subcortical, total brain (TBV), and intracranial (ICV) volumes between 472 subjects with DSM-IV ASD diagnoses and 538 healthy volunteers (age range: 6-64 years), obtained from high-resolution structural brain scans provided by the Autism Brain Imaging Data Exchange (ABIDE). Compared to healthy volunteers, we found significantly larger pallidum (Cohen's d=0.15) and lateral ventricle volumes (Cohen's d=0.18) in ASD. These enlargements were independent of total brain volume and IQ, passed FDR correction for multiple comparisons, and were observed in overall, male-only, and medication-free subjects. In addition, intracranial, hippocampal, and caudate volumes were enlarged in ASD at a nominal statistical threshold of p<0.05. This study provides the first robust evidence for pallidum enlargement in ASD independent from TBV and encourages further study of the functional role of the pallidum in individuals with autism spectrum disorder.

| S-EPMC5920514 | biostudies-literature

Cortical Thinning and Ventricle Enlargement in Neuromyelitis Optica Spectrum Disorders.

Project description:Background: In neuromyelitis optica spectrum disorders (NMOSDs), inflammation is not the sole driver of accumulation of disability; neurodegeneration is another important pathological process. We aim to explore different patterns of cortical atrophy and ventricular enlargement in NMOSD. Methods: We retrospectively analyzed a cohort of 230 subjects, comprising 55 healthy controls (HCs), 85 multiple sclerosis (MS), and 90 NMOSD patients from Tianjin Medical University General Hospital and Beijing Tiantan Hospital. Different compartments of the brain (total gray, cortex, subcortex gray, and ventricle volume) were evaluated with the FreeSurfer. Multiple linear regressions were adopted to explore associations between cortex volume and predict factors. Results: Compared with HCs, NMOSD, and MS displayed an enlarged lateral and third ventricle (p < 0.001), whereas expansion of the fourth ventricle was observed in MS rather than NMOSD (p = 0.321). MS and NMOSD patients exhibited cortical thinning in comparison with HCs. However, pronounced cortical atrophy were only significant in pre-cuneus, parahippocampal, and lateral occipital lobe between MS and NMOSD. Patients with NMOSD had decreased local gyrification index in orbitofrontal and pre-cuneus lobe, and reduced pial surface area. Linear regression analysis revealed cortex volume were predicated by advanced age (standardized β = -0.404, p = 0.001) as well as prolonged disease history (standardized β = -0.311, p = 0.006). Conclusion: NMOSD exhibited global cortex atrophy with enlarged lateral and third ventricles. Moreover, cortex volume is associated with age and disease duration.

| S-EPMC7481470 | biostudies-literature

Knockdown of Inner Arm Protein IC138 in Trypanosoma brucei Causes Defective Motility and Flagellar Detachment.

Project description:Motility in the protozoan parasite Trypanosoma brucei is conferred by a single flagellum, attached alongside the cell, which moves the cell forward using a beat that is generated from tip-to-base. We are interested in characterizing components that regulate flagellar beating, in this study we extend the characterization of TbIC138, the ortholog of a dynein intermediate chain that regulates axonemal inner arm dynein f/I1. TbIC138 was tagged In situ-and shown to fractionate with the inner arm components of the flagellum. RNAi knockdown of TbIC138 resulted in significantly reduced protein levels, mild growth defect and significant motility defects. These cells tended to cluster, exhibited slow and abnormal motility and some cells had partially or fully detached flagella. Slight but significant increases were observed in the incidence of mis-localized or missing kinetoplasts. To document development of the TbIC138 knockdown phenotype over time, we performed a detailed analysis of flagellar detachment and motility changes over 108 hours following induction of RNAi. Abnormal motility, such as slow twitching or irregular beating, was observed early, and became progressively more severe such that by 72 hours-post-induction, approximately 80% of the cells were immotile. Progressively more cells exhibited flagellar detachment over time, but this phenotype was not as prevalent as immotility, affecting less than 60% of the population. Detached flagella had abnormal beating, but abnormal beating was also observed in cells with no flagellar detachment, suggesting that TbIC138 has a direct, or primary, effect on the flagellar beat, whereas detachment is a secondary phenotype of TbIC138 knockdown. Our results are consistent with the role of TbIC138 as a regulator of motility, and has a phenotype amenable to more extensive structure-function analyses to further elucidate its role in the control of flagellar beat in T. brucei.

| S-EPMC4640498 | biostudies-literature

Schizophrenia-Related Microdeletion Impairs Emotional Memory through MicroRNA-Dependent Disruption of Thalamic Inputs to the Amygdala.

Project description:Individuals with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing psychiatric diseases such as schizophrenia. Individuals with 22q11DS and schizophrenia are impaired in emotional memory, anticipating, recalling, and assigning a correct context to emotions. The neuronal circuits responsible for these emotional memory deficits are unknown. Here, we show that 22q11DS mouse models have disrupted synaptic transmission at thalamic inputs to the lateral amygdala (thalamo-LA projections). This synaptic deficit is caused by haploinsufficiency of the 22q11DS gene Dgcr8, which is involved in microRNA processing, and is mediated by the increased dopamine receptor Drd2 levels in the thalamus and by reduced probability of glutamate release from thalamic inputs. This deficit in thalamo-LA synaptic transmission is sufficient to cause fear memory deficits. Our results suggest that dysregulation of the Dgcr8-Drd2 mechanism at thalamic inputs to the amygdala underlies emotional memory deficits in 22q11DS.

| S-EPMC5457478 | biostudies-literature

Microwave sensing dataset for noninvasive monitoring of ventricle enlargement due to Alzheimer's disease.

Project description:This paper presents a dataset generated from a comprehensive study on the potential of microwave imaging for early detection or monitoring of different stages of Alzheimer's disease. The study includes collecting and analyzing frequency-domain data using a radar-based head imaging system. The data was obtained from lamb brain phantoms designed to mimic lateral ventricle enlargement, a common symptom of Alzheimer's disease. The article provides detailed descriptions of the data collection method, experimental setup, and different phantoms used. Additionally, the article highlights the importance and potential of the dataset to be used for evaluating and validating new signal processing and imaging techniques. The dataset includes magnitude and phase information for both reflected and transmitted signals making it useful to evaluate radar-based signal processing and imaging techniques. The dataset is open-source and available to the scientific community, providing a valuable resource for researchers to advance their understanding of the potential use of microwave imaging techniques for detecting or monitoring Alzheimer's disease.

| S-EPMC9999157 | biostudies-literature

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome.

Project description:Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

| S-EPMC5136487 | biostudies-literature

Mutations in Hydin impair ciliary motility in mice.

Project description:Chlamydomonas reinhardtii hydin is a central pair protein required for flagellar motility, and mice with Hydin defects develop lethal hydrocephalus. To determine if defects in Hydin cause hydrocephalus through a mechanism involving cilia, we compared the morphology, ultrastructure, and activity of cilia in wild-type and hydin mutant mice strains. The length and density of cilia in the brains of mutant animals is normal. The ciliary axoneme is normal with respect to the 9 + 2 microtubules, dynein arms, and radial spokes but one of the two central microtubules lacks a specific projection. The hydin mutant cilia are unable to bend normally, ciliary beat frequency is reduced, and the cilia tend to stall. As a result, these cilia are incapable of generating fluid flow. Similar defects are observed for cilia in trachea. We conclude that hydrocephalus in hydin mutants is caused by a central pair defect impairing ciliary motility and fluid transport in the brain.

| S-EPMC2234243 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data