Ontology highlight
ABSTRACT:
PROVIDER: PRJEB63603 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| ERR11693095_1.fastq.gz | Fastqsanger.gz | |||
| ERR11693095_2.fastq.gz | Fastqsanger.gz | |||
| ERR11707315_1.fastq.gz | Fastqsanger.gz | |||
| ERR11707315_2.fastq.gz | Fastqsanger.gz |
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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
Project description:We developed a human cerebral organoid model derived from induced pluripotent stem cells (iPSCs) with targeted genome editing to abolish protein expression of the Contactin Associated Protein-like 2 (CNTNAP2) autism spectrum disorder (ASD) risk gene, mimicking loss-of-function mutations seen in patients. CNTNAP2-/- cerebral organoids displayed accelerated cell cycle, ventricular zone disorganisation and increased cortical folding. Proteomic analysis revealed disruptions in glutamatergic/GABAergic synaptic pathways and neurodevelopment, highlighting increased protein expression of corticogenesis and neurodevelopment-related genes such as Forkhead box protein G1 (FOXG1) and Paired box 6 (PAX6). Transcriptomic analysis revealed differentially expressed genes (DEG) belonging to inhibitory neuron-related gene networks. Interestingly, there was a weak correlation between the transcriptomic and proteomic data, suggesting nuanced translational control mechanisms. Along these lines we find upregulated Protein Kinase B (Akt)/mechanistic target of rapamycin (mTOR) signalling in CNTNAP2-/- organoids. Spatial transcriptomics analysis of CNTNAP2-/- ventricular zones demonstrated pervasive changes in gene expression, particularly in PAX6- cells, implicating upregulation of cell cycle regulation pathways, synaptic and glutamatergic/GABAergic pathways. We noted a significant overlap of all omics datasets with idiopathic ASD (macrocephaly) iPSC-derived telencephalic organoids DEG, where FOXG1 was upregulated, along with aberrant expression of Glutamate decarboxylase 1 (GAD1) and T-Box Brain Transcription Factor 1 (TBR1), suggesting altered GABAergic/glutamatergic neuron development. These findings potentially highlight a shared mechanism in the early cortical development of various forms of ASD, further elucidate the role of CNTNAP2 in ASD pathophysiology and cortical development and pave the way for targeted therapies using cerebral organoids as preclinical models.
2024-11-19 | PXD051473 | Pride
Project description:Brain organoids are promising tools for disease modelling and drug development. For proper neuronal network formation excitatory and inhibitory neurons as well as glia need to co-develop. Here we report the directed differentiation and self-organization of induced pluripotent stem cells in a collagen hydrogel towards a highly interconnected neuronal network in a macroscale tissue format. Bioengineered Neuronal Organoids (BENOs) comprise interconnected excitatory and inhibitory neurons as well as supportive astrocytes and oligodendrocytes. Giant depolarizing potential (GDP)-like events observed within 20-40 days of BENO culture mimic early network activity of the fetal brain. The switch from excitatory to inhibitory GABA activity, and reduced GDPs at >40 day BENO cultures indicate progressive neuronal network maturation. BENOs demonstrate expedited complex network burst development after two months of culture and provide the first evidence for long-term potentiation and plasticity in brain organoids. BENOs exhibit structural and functional properties similar to the fetal brain and thus may be explored as a model to study the development of neuronal plasticity.
2020-07-02 | GSE139101 | GEO
Project description:<p>Elucidating the cellular architecture of the human neocortex is central to understanding our cognitive abilities and susceptibility to disease. In this study, we applied single nucleus RNA sequencing to perform a comprehensive analysis of cell types in the middle temporal gyrus of human cerebral cortex. We identify a highly diverse set of excitatory and inhibitory neuronal types, many of which are relatively sparse. Additionally, we found that excitatory types are less layer-restricted than expected based prior knowledge from cell morphologies and from mouse studies. Comparison to a similar mouse cortex single cell RNA-sequencing dataset revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of human cell type properties. Despite this general conservation, we also find extensive differences between homologous cell types in human and mouse, including dramatic alterations in proportions, laminar distributions, gene expression, and morphology. These species-specific features emphasize the importance of directly studying human brain.</p> <p>This study conducted by the Allen Institute for Brain Science was supported by the Allen Institute for Brain Science and by US National Institutes of Health grant U01 MH114812-02 to E.S.L. Collaborators request that publications resulting from these data cite their original publication: Hodge RD, Bakken TE, et al. Conserved cell types with divergent features between human and mouse cortex. bioRxiv. 2018 doi: <a href="https://www.biorxiv.org/content/10.1101/384826v1" target="_blank">10.1101/384826</a>.</p>
| phs001790 | dbGaP
Project description:Loss of UBE3A impacts both neuronal and non-neuronal cells in human cerebral organoids.
| PRJNA1064612 | ENA
Project description:Cerebral organoids â three-dimensional cultures of human cerebral tissue derived from pluripotent stem cells â have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and novel interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages, and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue in order to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures. 734 single-cell transcriptomes from human fetal neocortex or human cerebral organoids from multiple time points were analyzed in this study. All single cell samples were processed on the microfluidic Fluidigm C1 platform and contain 92 external RNA spike-ins. Fetal neocortex data were generated at 12 weeks post conception (chip 1: 81 cells; chip 2: 83 cells) and 13 weeks post conception (62 cells). Cerebral organoid data were generated from dissociated whole organoids derived from induced pluripotent stem cell line 409B2 (iPSC 409B2) at 33 days (40 cells), 35 days (68 cells), 37 days (71 cells), 41 days (74 cells), and 65 days (80 cells) after the start of embryoid body culture. Cerebral organoid data were also generated from microdissected cortical-like regions from H9 embryonic stem cell derived organoids at 53 days (region 1, 48 cells; region 2, 48 cells) or from iPSC 409B2 organoids at 58 days (region 3, 43 cells; region 4, 36 cells).
2015-12-07 | E-GEOD-75140 | biostudies-arrayexpress
Project description:Human forebrain organoids (day 50) derived from U1M and U2F iPS cell lines were exposed with or without 1 mM valproic acid (VPA) for 72h. Organoids were then used for single cell RNA sequencing (scRNA-seq). Through data processing, ten major cell types including astrocyte, choroid plexus, endothelia, intermediate progenitor cells, medial ganglionic eminence, radial glia, immature neuron, excitatory and inhibitory neuron, and microglia-like cells were identified. We found that VPA affected gene expression in choroid plexus, excitatory neuron, immature neuron, and medial ganglionic eminence cells. The cell type-specific DEGs were enriched with mitotic nuclear division, multiple neuronal functions, and response to type I interferon and virus.
2021-10-31 | GSE186814 | GEO
Project description:Periventricular heterotopia (PH), the most common form of grey matter heterotopia, represents a cortical malformation that is often associated with developmental delay and drug-resistant seizures1,2. The detailed neurophysiological underpinnings of PH symptoms in humans remain, however, elusive. Human cerebral organoids (hCOs) derived from patients with causative mutations in FAT4 or DCHS1 exhibit key features of PH3, but neuronal activity in these 3D models has not yet been investigated. Here, using silicon probe recordings, we detected exaggerated spontaneous spike activity in FAT4 and DCHS1 hCOs, suggesting functional changes in neuronal networks. Patch-clamp recordings revealed a decreased spike threshold exclusively for DCHS1 neurons, which presumably results from an enhanced density of somatic voltage-gated sodium channels. Furthermore, single-cell morphological reconstructions and immunostainings demonstrated greater morphological complexity of neurons and synaptic alterations, rather than an imbalance of excitatory-inhibitory neuron number, as contributing to the hyperactivity observed in FAT4 and DCHS1 hCOs. The morphological phenotype was rescued by an expression of wild-type DCHS1 in DCHS1 neurons. In addition, transcriptome and proteome analyses uncovered changes in GO terms associated with neuronal morphology and synaptic function. Overall, we provide detailed new insights into cellular alterations likely contributing to the emergence of symptoms in grey matter heterotopia.
2025-01-13 | PXD038760 | Pride
Project description:Dysfunctional paracrine signaling through Pannexin 1 (PANX1) channels is linked to several adult neurological pathologies and emerging evidence suggests that PANX1 plays an important role in human brain development. It remains unclear how early PANX1 influences brain development, or how loss of PANX1 alters the developing human brain. Using a cerebral organoid model of early human brain development, we find that PANX1 is expressed at all stages of organoid development from neural induction through to neuroepithelial expansion and maturation. Interestingly, PANX1 cellular distribution and subcellular localization changes dramatically throughout cerebral organoid development. During neural induction, PANX1 becomes concentrated at the apical membrane domain of neural rosettes where it co-localizes with several apical membrane adhesion molecules. During neuroepithelial expansion, PANX1-/- organoids are significantly smaller than control and exhibit significant gene expression changes related to cell adhesion, WNT signaling and non-coding RNAs. As cerebral organoids mature, PANX1 expression is significantly upregulated and is primarily localized to neuronal populations outside of the ventricular-like zones. Ultimately, PANX1 protein can be detected in all layers of a 21-22 post conception week human fetal cerebral cortex. Together, these results show that PANX1 is dynamically expressed by numerous cell types throughout embryonic and early fetal stages of human corticogenesis and loss of PANX1 compromises neuroepithelial expansion due to dysregulation of cell-cell and cell-matrix adhesion, perturbed intracellular signaling, and changes to gene regulation.
2023-12-12 | GSE249624 | GEO
Project description:Human telencephalon is an evolutionary advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remains largely unknown. We generated human telencephalic organoids from stem cell-derived single neural rosettes (SNRs) and investigated telencephalic development under normal and pathological conditions. SNR-derived organoids contained pallial and subpallial neural progenitors (NPs), excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and demonstrated predictable organization and cytoarchitecture. We comprehensively characterized the properties of neurons in SNR-derived organoids and identified transcriptional programs associated with the specification of excitatory and inhibitory lineages from a common pool of NPs early in telencephalic development. We also demonstrated that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits associated with impaired expression of clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable new model for studying human telencephalic development and identifies novel molecular pathways disrupted by SHANK3 hemizygosity in human telencephalic tissue.
2022-08-23 | GSE211878 | GEO