Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β

ABSTRACT: Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, encodes a scaffold protein that has complex impacts on neuronal development. However, its role in neuronal polarization remains unclear. Here we show that phosphorylation of DISC1 at Ser58 and Ser713 regulates cortical neuron polarization¬. Expression of phosphor-dead human DISC1 (Ser58Ala, Ser713Ala; hDISC1AA) delays the transition from multipolar to uni/bipolar cells in mouse cortical culture. Mice carrying the hDISC1AA mutant exhibit aberrant orientation of the axon initial segment and reduced thickness of corpus callosum. hDISC1AA knock-in mice exhibit hyperlocomotion activity in an open field, deficits in prepulse inhibition, reduced social interaction, and defective novel object recognition. GSK3β activity is increased in the cortices of the hDISC1AA knock-in mice. Embryonic treatment of the GSK3β inhibitor SB-216763 rescues behavioral deficits in hDISC1AA/+ mice. Our findings support a model in which dual phosphorylation of DISC1 at Ser58 and Ser713 inhibits GSK3β activity and plays a crucial role in neural polarization, potentially contributing to the manifestation of psychiatric disorders related to DISC1 dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE230632 | GEO | 2025/04/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β

Project description:Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β

| PRJNA962027 | ENA

Transcriptional consequences of DISC1 knockdown in human neural progenitor cells

Project description:Background: One of the strongest identified risk factors for major psychiatric illness is a chromosomal translocation directly disrupting the DISC1 gene, which is observed in members of a large Scottish family. Although DISC1 is known to function through a variety of molecular pathways, no global assessment of the molecular consequences of cellular DISC1 perturbation has been carried out to date. Methods: Predicted effects of the t(1;11)(q42;q14) translocation on DISC1 expression were modelled in neural progenitor cells derived from human fetal cortex using RNA interference (RNAi). Downstream effects on the cellular transcriptome were assessed by microarray. The reproducibility of individual gene expression changes was tested in repeat experiments by quantitative PCR.Results: A total of 54 genes were differentially expressed between the DISC1 and control siRNA conditions at a false discovery rate (FDR) â¤ 0.05 in the primary experiment. Differentially expressed genes were significantly over-represented in Gene Ontology terms relating to the cell cycle, but included genes involved in a variety of other functions. Several genes showing reproducible differences in gene expression have been previously implicated in psychiatric disorders. Most consistent gene expression differences were seen for CCND2, MEG3, SPOCK2 and GABRA5. Total RNA extracted from human neural progenitor cells manipulated with either of two siRNAs: control siRNA or siRNA targeting DISC1 . 3 replicates per group. Genome wide transcript levels were then measured using gene expression microarrays.

2016-03-01 | E-GEOD-35548 | biostudies-arrayexpress

RNA-seq of oligodendroglia progenitor cells(OPCs) isolated from WT and DISC1-Δ3 mice

Project description:Disrupted-in-schizophrenia-1 (DISC1), as one of the schizophrenia susceptibility genes highly expressed in oligodendrocyte precursor cells (OPCs), impacts oligodendroglial differentiation and myelination. Several DISC1 splicing variants, including DISC1-Δ3 (a DISC1 transcript with deleted exon 3 in a single allele), are abnormally upregulated in human schizophrenia patients, however, how they trigger the onset of the disease has not been explored yet. Here, we generate a mouse line that mimics human DISC1-Δ3 in oligodendrocyte lineage cells, and demonstrate that hypertrophic OPCs rather than myelin, are responsible for the neuronal deficits and schizophrenia-like symptoms. RNAseq was performed to analyze the transcriptome change in DISC1-Δ3 OPC, revealing that DISC1-Δ3 elevates the Wnt pathway activity in OPCs, which promotes Wif1 expression, thereby leading to disrupted synapse formation in neighboring neurons. Interfering or knockout of Wif1 in DISC1-Δ3 OPCs could rescue neuronal synaptic and functional deficits in our mouse model. Our findings shed light on the myelination-independent role of OPCs on the onset of schizophrenia, and may pave the way for new rational lines of inquiry in developing therapeutic strategies for schizophrenia.

2022-12-28 | GSE183341 | GEO

Transcriptional dysregulation of synaptic genes in a human iPSC model of major mental disorders

Project description:Schizophrenia and other psychiatric disorders are postulated to be developmental disorders resulting from synapse dysfunction. How susceptibility genes for major mental disorders could lead to synaptic deficits in humans is not well-understood. Here we generated induced pluripotent stem cells (iPSCs) from four members of a family in which a frame-shift mutation of Disrupted-in-schizophrenia-1 (DISC1) co-segregated with psychiatric disorders and further produced different isogenic iPSC lines via genetic editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPSC-derived forebrain neurons. Mechanistically, mutant DISC1 dysregulates the expression of many genes related to synapses and psychiatric disorders and depletes wild-type DISC1 and the NCoR1 transcription co-repressor complex. Furthermore, mechanism-guided pharmacological inhibition of phosphodiesterases rescues synaptic defects in mutant neurons. Our study uncovers a novel gain-of-function mechanism through which the psychiatric disorder-relevant mutation affects synaptic functions via transcriptional dysregulation and provides insight into the molecular and synaptic etiopathology of psychiatric disorders. Two patient derived iPSC lines carrying heterozygous 4bp deletion in DISC1 gene and 1 related control were analyzed in biological triplicate

2014-08-01 | E-GEOD-57821 | biostudies-arrayexpress

Transcriptional consequences of DISC1 knockdown in human neural progenitor cells

Project description:Background: One of the strongest identified risk factors for major psychiatric illness is a chromosomal translocation directly disrupting the DISC1 gene, which is observed in members of a large Scottish family. Although DISC1 is known to function through a variety of molecular pathways, no global assessment of the molecular consequences of cellular DISC1 perturbation has been carried out to date. Methods: Predicted effects of the t(1;11)(q42;q14) translocation on DISC1 expression were modelled in neural progenitor cells derived from human fetal cortex using RNA interference (RNAi). Downstream effects on the cellular transcriptome were assessed by microarray. The reproducibility of individual gene expression changes was tested in repeat experiments by quantitative PCR.Results: A total of 54 genes were differentially expressed between the DISC1 and control siRNA conditions at a false discovery rate (FDR) ≤ 0.05 in the primary experiment. Differentially expressed genes were significantly over-represented in Gene Ontology terms relating to the cell cycle, but included genes involved in a variety of other functions. Several genes showing reproducible differences in gene expression have been previously implicated in psychiatric disorders. Most consistent gene expression differences were seen for CCND2, MEG3, SPOCK2 and GABRA5.

2016-03-01 | GSE35548 | GEO

DISC1 Protects Against Zika Virus Infection and Long-Term Neurological Damage Through AMPK-mTOR-Mediated Autophagy

Project description:Disrupted in Schizophrenia 1 (DISC1) is essential for neuronal development and has been implicated in various psychiatric disorders. However, its role in Zika virus (ZIKV) infection, particularly in congenital Zika syndrome (CZS) and ZIKV-induced long-term neurodevelopmental defects, remains unexplored. In this study, we demonstrate that DISC1 suppresses ZIKV infection in human placental and neuroglia cells, as well as in murine macrophages. DISC1 also limits ZIKV dissemination from peripheral tissues to key organs of mice, including the uterus, testis, and brain, thereby reducing fetal abortion rates and intrauterine growth restriction. Notably, DISC1 is associated with long-term ZIKV effects, including memory loss, reduced anxiety and depression, declines in sociability and social novelty. Mechanistically, DISC1 activates autophagy by enhancing AMPKα phosphorylation and reducing mTOR phosphorylation, protecting against ZIKV infection. Additionally, DISC1 interacts with LC3 to further activate autophagy, partially contributing to inhibit ZIKV infection. In conclusion, DISC1 plays a critical factor in controlling ZIKV infection and mitigating CZS and ZIKV-induced neurocognitive decline.

2025-02-17 | GSE289385 | GEO

Endogenous Cell Type-Specific DISC1 Interactomes Reveal Protein Networks Associated to Neurodevelopmental Disorders

Project description:Disrupted in schizophrenia 1 (DISC1) has been implicated in contributing to a number of psychiatric diseases and neurodevelopmental phenotypes such as the proliferation and differentiation of neural progenitor cells. While there has been significant effort directed towards understanding the function of DISC1 through the determination of its protein-protein interactions within an in-vitro setting, endogenous interactions involving DISC1 within a cell-type specific setting relevant to neural development remain unclear.

2018-07-04 | PXD007103 | Pride

Transcriptional dysregulation of synaptic genes in a human iPSC model of major mental disorders

2014-08-01 | GSE57821 | GEO

Transcriptome profiling of human neural progenitor cells and neurons with DISC1 interruption

Project description:Purpose: Genetic and clinical association studies have identified disrupted-in-schizophrenia 1 (DISC1) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) translocation in a Scottish family, in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We sought to compare the gene expression profiles of human neural progenitor cells (NPCs) and neurons with interruption of the DISC1 gene in exon 2 (affecting all known coding transcripts) or exon 8 (near the site of the Scottish translocation, affecting longer transcripts). Methods: Wild-type and DISC1-targeted iPSCs (wild-type = "WT", exon 8 single allelic frameshift mutant = "ex8_wm", exon 8 biallelic frameshift mutant = "ex8_mm", exon 2 biallelic frameshift mutant = "ex2mm") were differentiated to NPCs and neurons using an embryoid aggregate method. NPC or neuronal cultures were used for RNA harvest and subsequent paired-end stranded sequencing of >50M reads/sample and 3-6 biological replicates per group. Results: We find that a subset of genes related to neuronal differentiation and development are dysregulated with DISC1 disruption at the NPC timepoint, whereas expression of genes related to neuronal function and signaling are altered at the neuronal timepoint. This study implicates DISC1 as a regulator of neuronal development. mRNA profiles of wild-type and DISC1-targeted human iPSC-derived neural progenitor cells (day 17) and neurons (day 50) by paired-end sequencing, with 3-6 biological replicates, using Illumina HiSeq

2015-09-14 | E-GEOD-71289 | biostudies-arrayexpress

Human Neuron Proteome Altered by Disrupted in schizophrenia 1 (DISC1) Mutations

Project description:Disrupted in schizophrenia 1 is a protein that is encoded by the DISC1 gene in humans. In coordination with a wide array of interacting partners, DISC1 has been shown to participate in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, synapse formation and maturation, synaptic transmission, mitochondrial transport, fission and/or fusion, and cell-to-cell adhesion. Several studies have shown that unregulated expression or altered protein structure of DISC1 may predispose individuals to the development of schizophrenia, major depression, bipolar disorder, and other psychiatric conditions. The cellular functions that are disrupted by permutations in DISC1, which lead to the development of these disorders, have yet to be clearly defined and are the subject of current ongoing research.

2021-09-08 | PXD013391 | Pride

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