Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Autism-linked Cullin3 germline haploinsufficiency severely impacts mouse brain development and cortical neurogenesis through RhoA signaling

ABSTRACT: Autism-linked Cullin3 germline haploinsufficiency severely impacts mouse brain development and cortical neurogenesis through RhoA signaling

PROVIDER: PRJNA602627 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR10950400_1.fastq.gz	Fastqsanger.gz
	SRR10950400_2.fastq.gz	Fastqsanger.gz
	SRR10950401_1.fastq.gz	Fastqsanger.gz
	SRR10950401_2.fastq.gz	Fastqsanger.gz
	SRR10950402_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 218

Similar Datasets

Autism-linked Cullin3 germline haploinsufficiency severely impacts mouse brain development and cortical neurogenesis through RhoA signaling

Project description:E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for Neurodevelopmental Disorders such as Autism Spectrum Disorder (ASD) and Developmental Delay (DD). This study identifies the impact of the ASD-associated de novo Cul3-mutation on brain anatomy, behavior, molecular, cellular, and circuit-level mechanisms during early neocortical development. We report that Cul3 mutant mice have microcephaly and severe brain structure defects. This mouse model exhibits social and cognitive deficits and hyperactivity behavior. Spatiotemporal transcriptomic and proteomic profiling of Cul3 mouse brain implicates neurogenesis and cytoskeletal defects as key drivers of Cul3 functional effect. We show that Cul3 is critical for neuron growth and development. Cultured cortical neurons from the mutant mice have reduced dendritic length, actin cytosketon defects, reduced network activity, and increased cell death. At the molecular level, we implicate upregulation of small GTPase RhoA, involved in regulation of cytoskeletal dynamics, and neurite outgrowth as one of the pathways impacted by the de novo Cul3 mutations in ASD. Treatment with small molecule RhoA inhibitor Rhosin rescues dendrite length phenotype and implicates RhoA pathway in ASD.

2021-03-16 | GSE144046 | GEO

Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

Project description:E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for neurodevelopmental disorders including autism spectrum disorder (ASD) and developmental delay (DD). We generated Cul3-haploinsufficient mouse model to investigate brain anatomy, behavior, molecular, cellular, and circuit-level mechanisms dysregulated by Cul3 mutations. Spatiotemporal transcriptomic and proteomic profiling of the brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Quantitative proteomic profiling was performed by Tandem Mass Tag (TMT) labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis with SPS-MS3 workflow.

2020-01-22 | MSV000084830 | MassIVE

Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling.

Project description:E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.

| S-EPMC8443683 | biostudies-literature

A dual functions of autism-related chromatin remodeler CHD8 in developmental and adult neurogenesis

Project description:The loss-of-function mutations in the chromatin remodeler CHD8, a high-risk factor in autism spectrum disorder (ASD), lead to severe developmental delay, however, the underlying mechanisms remains elusive. Here, we use transcriptome and genomic occupancy reveal that CHD8 regulates chromatin accessibility and activates neurogenesis-related genes for cortical neurogenesis.

2022-10-17 | GSE148608 | GEO

CHD8 haploinsufficiency alters the developmental trajectories of human excitatory and inhibitory neurons linking autism phenotypes with transient cellular defects

Project description:Chromodomain helicase DNA-binding 8 (CHD8) is one of the most frequently mutated genes causative of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly and hence implicates cortical abnormalities in this form of ASD, the neurodevelopmental impact of human CHD8 haploinsufficiency remains unexplored. Here we combined human cerebral organoids and single cell transcriptomics to define the effect of ASD-linked CHD8 mutations on human cortical development. We found that CHD8 haploinsufficiency causes a major disruption of neurodevelopmental trajectories with an accelerated generation of inhibitory neurons and a delayed production of excitatory neurons alongside the ensuing protraction of the proliferation phase. This imbalance may contribute to the significant enlargement of cerebral organoids in line with the macrocephaly observed in patients with CHD8 mutations. By adopting an isogenic design of patient-specific mutations and mosaic cerebral organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Finally, our results assign different CHD8-dependent molecular defects to particular cell types, pointing to an abnormal and extended program of proliferation and alternative splicing specifically affected in, respectively, the radial glial and immature neuronal compartments. By identifying temporally restricted cell-type specific effects of human CHD8 mutations, our study uncovers developmental alterations as reproducible endophenotypes for neurodevelopmental disease modelling.

2024-01-27 | E-MTAB-11406 | biostudies-arrayexpress

CRISPR activation rescues electrophysiological abnormalities in SCN2A haploinsufficiency associated autism spectrum disorder

Project description:CRISPR activation rescues electrophysiological abnormalities in SCN2A haploinsufficiency associated autism spectrum disorder

| PRJNA796834 | ENA

Autism genes converge on microtubule biology and RNA-binding proteins during excitatory neurogenesis

Project description:Recent studies have identified a large number of high confidence (hc) autism spectrum disorder (ASD) genes. Systems biological and functional analyses have consistently implicated excitatory neurogenesis. However, the extent to which hcASD genes are involved in this process has not been explored systematically nor have the underlying biological pathways. Here, we leveraged CROP-Seq to repress 87 hcASD genes in an in vitro model of cortical neurogenesis. We identified 17 hcASD genes whose repression significantly alters developmental trajectory and results in a common cell state characterized by disruptions in proliferation and differentiation, cell cycle occupancy, mitotic spindle and microtubule biology, and RNA-binding proteins (RBPs). We also identified over 3,000 differentially expressed genes, 286 of which have expression profiles correlated with changes in developmental trajectory. Collectively, these genes again highlight microtubule biology and RBPs. Overall, we uncover transcriptional disruptions downstream of hcASD gene perturbations and correlate these disruptions with distinct differentiation phenotypes, while reinforcing neurogenesis, microtubule biology, and RBPs as convergent points of disruption in ASD.

2023-12-22 | GSE250378 | GEO

MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention

Project description:MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiologic defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.

2023-02-20 | PXD037867 | Pride

TAB2 haploinsufficiency

Project description:TAB2 haploinsufficiency

| PRJNA747894 | ENA

RhoA inhibitor treatment of spinal cord injury: Deep inside mechanism understanding for a better use

Project description:The present study shows by in vivo experiments, the impact of RhoA inhibitor treatment using a functionalized alginate scaffold and the beneficial results at the early stage by increasing neurites outgrowth and synaptic contact. However, 7 days after treatment a plateau is obtained in BBB score. We thus performed an in vitro and proteomic associated to systemic biology analyses of secreted factors from ND7/23 DRG cell line incubated with secreted factors from different segments after spinal cord lesion treated wih RhoA inhibitor. We then performed a time course proteomic study from the DRG cells in same conditions as for the secretome. The results taken together allow a better understanding of the mechanisms occurring in both side of the lesion and led a positive impact of the treatment on growth cone guidance in both sides of the lesion (Rostral 1 and Caudal 1). We identified the transcription factors involved in time course at the beginning of the treatment and the growth cone factors (receptors, ligands, signaling pathways) implicated in this time course. We also demonstrate the involvement of immunoglobulins (IgG1, IgG2) in this process. Anti-GFAP seem to bind to its own receptor in DRG cells when neurite outgrowth is initiated and thus modulate the process like in traumatic brain injury. These results open the door of a concomitant treatment at both sides of the lesion with RhoA inhibitor. However, we also pointed that RhoA inhibitor treatment led to an inhibition of several factors implicated in neurogenesis reflecting a global inhibition at term as detected in vivo that reached 2 weeks after treatment. RhoA inhibitor treatment is useful to initiate the neurogenesis process but needs to be supplied by a second treatment for increasing synaptic connections and the neuron reconnections.

2017-07-28 | PXD004639 | 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