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Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes [scRNA-seq]

ABSTRACT: 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+B50:B51 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118697 | GEO | 2022/08/11

REPOSITORIES: GEO

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Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes [bulk RNA-seq2]

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

Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes [bulk RNA-seq1]

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+B50:B51 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.

2022-08-11 | GSE210959 | GEO

RNA-seq of progenitors and neurons sorted from brain organoids

Project description:During development of the human cerebral cortex, multipotent neural progenitors generate excitatory neurons and glial cells. This process is faithfully recapitulated in brain organoids. By using telencephalic brain organoids grown using a dual reporter cell line to isolate neural progenitors and neurons we generated a cell type and developmental stage-specific transcriptome dataset..

2022-10-06 | GSE214654 | GEO

ATAC-seq of progenitors and neurons from human brain organoids

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FOXP1 Orchestrates Neurogenesis in Human Cortical Basal Progenitors

Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of Forkhead Box P1, in human iPSC-derived forebrain organoids with and without FOXP1. We generated cell type-specific gene expression profiles of FOXP1 in progenitors and excitatory neurons of dorsal telencephalic lineage.

2023-06-06 | GSE195510 | GEO

Transcriptome and proteome analysis of human brain organoids

Project description:During development of the human cerebral cortex, multipotent neural progenitors generate excitatory neurons and glial cells. Investigations of the transcriptome and epigenome have revealed important gene regulatory networks underlying this crucial developmental event. However, the post-transcriptional control of gene expression and protein abundance during human corticogenesis remains poorly understood. We addressed this issue by using a dual reporter cell line to isolate neural progenitors and neurons from the telencephalic brain organoid tissue and performed cell type and developmental stage-specific transcriptome and proteome analysis. Integrating the two datasets revealed temporal modules of gene expression during human corticogenesis, both at RNA and protein level. Our multiomics approach reveals novel posttranscriptional regulatory mechanisms crucial for fidelity of cortical development.

2022-10-25 | PXD037106 | Pride

ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum

Project description:Human telencephalic organoids derived from iPSC lines: control and harboring heterozygous ARID1B mutations.

2023-12-01 | GSE231546 | GEO

Subcellular and regional localization of mRNA translation in midbrain dopamine neurons

Project description:Local translation within excitatory and inhibitory neurons is known to be involved in neuronal development and synaptic plasticity. Despite the extensive dendritic and axonal arborizations of monoaminergic neurons, the subcellular localization of protein synthesis has not been well-characterized in these populations. Here, we investigated mRNA localization in midbrain dopaminergic (mDA) neurons, cells with enormous axonal and dendritic projections, both of which can release dopamine (DA). Using highly-sensitive sequencing and imaging approaches in mDA axons, we found no evidence for axonal mRNA localization or translation. In contrast, we found that mDA neuronal dendritic projections into the substantia nigra reticulata (SNr) contain ribosomes and mRNAs encoding the DA synthesis, release, and reuptake machinery. Surprisingly, we found dendritic localization of mRNAs encoding synaptic vesicular release proteins in mDA neurons. Our results are consistent with a role for local translation in the regulation of DA transmission from dendrites, but not striatal axons. Finally, we defined a molecular signature of sparse mDA neurons in the SNr, including enrichment of an ER calcium pump previously undescribed in mDA neurons.

2021-07-27 | GSE180913 | 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

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Project description:Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing "leak" current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual SNr neurons. We discovered that SNr neurons express the sodium leak current, NaLCN and that SNr neurons lacking NaLCN have impaired spontaneous firing.

2016-05-13 | GSE78521 | GEO

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