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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE144046 | GEO | 2021/03/16

REPOSITORIES: GEO

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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

Cortical organoids model early brain development disrupted by 16p11.2 CNV in autism

Project description:Reciprocal deletion and duplication of 16p11.2 is the most common copy number variation (CNV) associated with Autism Spectrum Disorder (ASD) and other developmental disorders, and has significant effect on brain size. We used cortical organoids derived from ASD cases to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. We show that organoids recapitulate patients’ macrocephaly and microcephaly phenotypes. Deletions and duplications have “mirror” effects on cell proliferation, maturation and synapse number, consistent with “mirror” effects on brain development in humans. Neuronal migration was decreased in both, deletion and duplication organoids. Transcriptomic and proteomic profiling revealed synaptic defects and neuronal migration as key drivers of 16p11.2 functional effect. We implicate upregulation of small GTPase RhoA involved in regulation of cytoskeletal dynamics, neuron migration and neurite outgrowth as one of the pathways impacted by the 16p11.2 CNV in ASD. Treatment with the RhoA inhibitor Rhosin rescued neuron migration, but not synaptic defects. This study identifies pathways dysregulated by the 16p11.2 CNV during early neocortical development using cortical organoid models. Grant ID: Simons Foundation, #345469 Grant Title: Translational dysregulation of the RhoA pathway in autism Affiliation: University of California San Diego Name: Lilia M. Iakoucheva; Alysson R. Muotri

2021-07-31 | GSE142174 | GEO

The chromatin modifier CHD8 targets autism risk genes during human neurodevelopmentM-BM-

Project description:Whole-exome sequencing studies have implicated chromatin modifiers and transcriptional regulators in autism spectrum disorder (ASD) through the identification of de novo loss of function mutations in affected individuals. Many of these genes are co-expressed in mid-fetal human cortex, suggesting ASD risk genes converge in regulatory networks that are perturbed in ASD during neurodevelopment. To elucidate such networks we mapped promoters and enhancers bound by the chromodomain helicase CHD8, which is strongly enriched in ASD-associated de novo loss of function mutations, using ChIP-seq in mid-fetal human brain, human neural stem cells (hNSCs), and embryonic mouse cortex. We find that CHD8 targets are strongly enriched for ASD risk genes that converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in significant dysregulation of ASD risk genes targeted by CHD8, as well as additional genes important for neurodevelopment, including members of the Wnt/M-NM-2-catenin signaling pathway. Integration of CHD8 binding data with genetic and gene co-expression data in ASD risk models provides support for additional ASD risk genes. Together, our results suggest that loss of CHD8 function contributes to ASD through regulatory perturbation of other ASD risk genes during human cortical development. Two biological replicates for each ChIP with appropriate Input control Four biological replicates for each condition in knockdown experiments (Ctrl construct, Chd8 target C, and Chd8 target G)

2015-01-21 | E-GEOD-57369 | biostudies-arrayexpress

Microarray for density study of mouse Adipose-derived Stromal Cells (ASCs)

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2011-01-16 | E-GEOD-19924 | biostudies-arrayexpress

Proteomic Explorations of Autism Brain - Part 1

Project description:Autism Spectrum Disorder (ASD) is a group of common neurodevelopmental conditions with impairments in socialization, communication and restricted behaviors. Only a minority of ASD cases are determined to have a definitive etiology and the pathogenesis of most ASD remains poorly understood. In this study, we made use of the power of proteomics, heretofore little utilized in the study of the biology of ASD, and analyzed the proteomes of two brain regions, Brodmann area 19 (BA19) and posterior inferior cerebellum (CB), from 9 idiopathic ASD cases/9 matched controls by label-free HPLC-tandem mass spectrometry (MS) and validated the differentially expressed protein findings with selected-reaction monitoring MS. The data revealed marked differences between ASD and control brain proteomes for both brain regions, with numerous differentially expressed proteins, although the proteomic difference between brain regions was not attenuated in ASD brain. Bioinformatic analyses based on the differentially expressed proteins highlighted multiple canonical pathways and protein-protein interaction networks that are implicated in the differential biology of ASD vs. controls. Canonical pathways involving glutamate receptor signaling and RXR activation were enriched for both BA19 and CB; others such as cell-cell junction signaling and fatty acid oxidation were enriched for BA19 and CB, respectively. Network analysis revealed a protein interaction network related to synaptic biology in BA19 and another involving cytoskeletal/vesicular functions in CB. Upstream regulator analysis for both regions revealed multiple neurodegeneration-associated proteins. The finding of several shared canonical pathways and upstream regulators for both regions underscores likely common ASD pathophysiology that has distinctive regional expression.

2019-09-16 | PXD012755 | Pride

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

Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors

Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remains undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes a new ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

2021-05-23 | GSE173262 | GEO

Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease relevant pathologies

Project description:There are hundreds of risk genes for autism spectrum disorder (ASD), but signaling networks at the protein level remain unexplored. We used neuron-specific proximity-labeling proteomics (BioID) to identify protein-protein interaction (PPI) networks for 41 ASD-risk genes. Neuron-specific PPI networks included synaptic transmission proteins, which are disrupted by de novo missense variants. The PPI network map revealed convergent pathways including mitochondrial/metabolic processes, Wnt signaling, ion channel activity and MAPK signaling. CRISPR knockout validations revealed an association between mitochondrial activity and ASD-risk genes. The PPI network showed an enrichment of 112 additional ASD-risk genes and differentially expressed genes from post-mortem ASD patients. Clustering of risk genes based on PPI networks identified gene groups corresponding to clinical behavior score severity. Our data reveal that cell type-specific PPI networks can identify previously unknown individual and convergent ASD signaling networks, provide a method to assess patient variants, and reveal biological insight into disease mechanisms and sub-cohorts of ASD.

2022-09-24 | GSE213899 | GEO

The chromatin modifier CHD8 targets autism risk genes during human neurodevelopment

Project description:Whole-exome sequencing studies have implicated chromatin modifiers and transcriptional regulators in autism spectrum disorder (ASD) through the identification of de novo loss of function mutations in affected individuals. Many of these genes are co-expressed in mid-fetal human cortex, suggesting ASD risk genes converge in regulatory networks that are perturbed in ASD during neurodevelopment. To elucidate such networks we mapped promoters and enhancers bound by the chromodomain helicase CHD8, which is strongly enriched in ASD-associated de novo loss of function mutations, using ChIP-seq in mid-fetal human brain, human neural stem cells (hNSCs), and embryonic mouse cortex. We find that CHD8 targets are strongly enriched for ASD risk genes that converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in significant dysregulation of ASD risk genes targeted by CHD8, as well as additional genes important for neurodevelopment, including members of the Wnt/β-catenin signaling pathway. Integration of CHD8 binding data with genetic and gene co-expression data in ASD risk models provides support for additional ASD risk genes. Together, our results suggest that loss of CHD8 function contributes to ASD through regulatory perturbation of other ASD risk genes during human cortical development.

2015-01-21 | GSE57369 | GEO

Cerebral Cavernous Malformation Proteins and MEKK3 Coordinately Modulate SMURF1 Abundance to Control RhoA-dependent Endothelial Cell Phenotypic State

Project description:Cerebral Cavernous Malformations (CCM), caused by loss of CCM1, CCM2 or CCM3 in endothelial cells (ECs), are leaky capillaries causing seizures and stroke. CCM protein loss gives overlapping changes in biomechanical and transcriptional properties of ECs, due to common RhoA-driven alterations in cytoskeletal organization and intracellular signaling. However, EC models of 3-D tube formation show loss of each CCM protein generates distinct morphological defects in tubular structures. Computational modeling, live-cell imaging and RNA sequencing revealed distinct functional roles of CCM1 and CCM3 in regulating EC-EC and EC-matrix interactions. CCM2 has an intermediate phenotype consistent with its interaction with CCM1 and CCM3. In ECs, CCM proteins regulate SMURF1 E3 ligase ubiquitination and degradation of RhoA. Loss of CCM proteins results in loss of SMURF1 and a concomitant increase of MEKK3, a negative regulator of SMURF1 expression. We propose CCM lesions develop because of dysregulated SMURF1 resulting in RhoA and MEKK3 gain-of-function.

2019-04-05 | GSE112882 | GEO

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