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Modeling the functional genomics of autism using human neurons.

ABSTRACT: We examined whether a human neuronal culture system could be used to assess the transcriptional program involved in human neural differentiation and in modeling some of the molecular features of a neurodevelopmental disorder such as autism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE28046 | GEO | 2011/06/01

SECONDARY ACCESSION(S): PRJNA139759

REPOSITORIES: GEO

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Modeling the functional genomics of autism using human neurons.

Project description:We examined whether a human neuronal culture system could be used to assess the transcriptional program involved in human neural differentiation and in modeling some of the molecular features of a neurodevelopmental disorder such as autism. Primary normal human neuronal progenitors differentiation for 0, 2, 4, or 8 weeks.

2011-06-01 | E-GEOD-28046 | biostudies-arrayexpress

Transcriptome study in Sicilian patients with autism spectrum disease

Project description:Ultimately, autism is classified as an early neurodevelopmental disorder, highly heterogeneous and with a heritability of between 40% and 90%. Transcriptome studies have already been done in subjects with autism, but we decided to perform such a study on our own cohort of Sicilian subjects with autism. the results obtained show the involvement of differentially expressed genes involving inflammatory mechanisms and the mitochondrilae system.

2024-09-09 | E-MTAB-13871 | biostudies-arrayexpress

Modeling the functional genomics of autism using human neurons.

Project description:Human neural progenitors from a variety of sources present new opportunities to model aspects of human neuropsychiatric disease in vitro. Such in vitro models provide the advantages of a human genetic background combined with rapid and easy manipulation, making them highly useful adjuncts to animal models. Here, we examined whether a human neuronal culture system could be utilized to assess the transcriptional program involved in human neural differentiation and to model some of the molecular features of a neurodevelopmental disorder, such as autism. Primary normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors and whole-genome gene expression was examined throughout a time course of neuronal differentiation. After 4 weeks of differentiation, a significant number of genes associated with autism spectrum disorders (ASDs) are either induced or repressed. This includes the ASD susceptibility gene neurexin 1, which showed a distinct pattern from neurexin 3 in vitro, and which we validated in vivo in fetal human brain. Using weighted gene co-expression network analysis, we visualized the network structure of transcriptional regulation, demonstrating via this unbiased analysis that a significant number of ASD candidate genes are coordinately regulated during the differentiation process. As NHNPs are genetically tractable and manipulable, they can be used to study both the effects of mutations in multiple ASD candidate genes on neuronal differentiation and gene expression in combination with the effects of potential therapeutic molecules. These data also provide a step towards better understanding of the signaling pathways disrupted in ASD.

| S-EPMC3170664 | biostudies-literature

Modeling Synaptic Mechanisms of Autism-associated Neuroligin-3 R451C Mutation Using Human Neurons

Project description:Synaptic dysfunction represents a key pathophysiology in neurodevelopmental disorders such as autism spectrum disorder (ASD). Rare mutation R451C in human Neuroligin 3 (NLGN3, encoded by X-linked gene NLGN3), a cell adhesion molecule essential for synapse formation, has been linked to ASD. Despite success in recapitulating the social interaction behavioral deficits and the underlying synaptic abnormalities in mouse model, the impact of NLGN3 R451C on the human neuronal system remains elusive. Here, we generated isogenic knock-in human pluripotent stem cell lines harboring NLGN3 R451C allele and examined its impact on synaptic transmission. Analysis of co-cultured excitatory and inhibitory induced neurons (iNs) with mutation revealed an augmentation in excitatory synaptic strength comparing to isogenic control, but not in inhibitory synaptic transmission. Consistently, the augmentation in excitatory transmission was confirmed in iNs transplanted into mouse forebrain. Using single-cell RNA seq on co-cultured excitatory and inhibitory iNs, we identified differential expression genes (DEGs) and found NLGN3 R451C alters gene networks associated with synaptic transmission. Gene ontology and enrichment analysis revealed convergent gene networks associated with ASD and other mental disorders. Our finding suggests that the NLGN3 R451C mutation could preferentially impact excitatory neurons, which causes overall network properties changes and excitation-inhibition imbalance related to mental disorders.

2022-10-26 | GSE180751 | 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.

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Multiplexed single-cell autism modeling reveals convergent mechanisms altering neuronal differentiation

Project description:We coupled dCas9-based transcriptional repression of autism and neurodevelopmental disease genes to single-cell RNA-sequencing in the context of human neuron differentiation to identify the unique and shared consequences of these perturbations in a pooled experimental format.

2020-06-20 | GSE142078 | GEO

Modeling Synaptic Mechanisms of Autism-associated Neuroligin-3 R451C Mutation Using Human Neurons

Project description:Modeling Synaptic Mechanisms of Autism-associated Neuroligin-3 R451C Mutation Using Human Neurons

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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

Modeling neurodevelopmental disorder-associated human AGO1 mutations in C. elegans Argonaute alg-1.

Project description:Modeling neurodevelopmental disorder-associated human AGO1 mutations in C. elegans Argonaute alg-1.

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Co-ordinate inhibition of autism candidate genes by topoisomerase inhibitors [Seq]

Project description:Topoisomerases are necessary for the expression of neurodevelopmental genes, and are mutated in some patients with autism spectrum disorder (ASD). We have studied the effects of inhibitors of Topoisomerase 1 (Top1) and Topoisomerase 2 (Top2) enzymes on mouse cortical neurons. We find that topoisomerases selectively inhibit long genes (>100kb), with little effect on all other gene expression. Using ChIPseq against RNA Polymerase II (Pol2) we show that the Top1 inhibitor topotecan blocks transcriptional elongation of long genes specifically. Many of the genes inhibited by topotecan are candidate ASD genes, leading us to propose that topoisomerase inhibition might contribute to ASD pathology. [Mouse] 5 biological replicates of transcriptome sequencing (RNAseq) from topotecan treated neurons and vehicle treated controls; Pol2 ChIPseq of topotecan and vehicle treated neurons [Human] Transcriptome sequencing (RNAseq) from topotecan treated neurons and vehicle treated control.

2013-08-30 | E-GEOD-43526 | biostudies-arrayexpress

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