A molecular and cellular perspective on human brain evolution and tempo

Nature, Год журнала: 2024, Номер 630(8017), С. 596 - 608

Опубликована: Июнь 19, 2024

Язык: Английский

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Generation of human cerebral organoids with a structured outer subventricular zone

Cell Reports, Год журнала: 2024, Номер 43(4), С. 114031 - 114031

Опубликована: Апрель 1, 2024

Outer radial glia (oRG) emerge as cortical progenitor cells that support the development of an enlarged outer subventricular zone (oSVZ) and expansion neocortex. The in vitro generation oRG is essential to investigate underlying mechanisms human neocortical expansion. By activating STAT3 signaling pathway using leukemia inhibitory factor (LIF), which not expressed guided organoids, we define a organoid differentiation method from pluripotent stem (hPSCs) recapitulates pool into oSVZ. oSVZ comprises expressing specific markers such GFAP, LIFR, HOPX, closely matching fetal oRG. Finally, incorporating neural crest-derived LIF-producing pericytes organoids effects LIF treatment. These data indicate increasing cellular complexity microenvironment promotes emergence supports platform study hPSC-derived brain routinely.

Язык: Английский

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Molecular and cellular dynamics of the developing human neocortex

Nature, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

The development of the human neocortex is highly dynamic, involving complex cellular trajectories controlled by gene regulation1. Here we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 neocortical samples encompassing both prefrontal cortex primary visual cortex. These span five main developmental stages, ranging first trimester to adolescence. In parallel, performed spatial transcriptomic analysis on a subset illustrate organization intercellular communication. This atlas enables us catalogue cell-type-specific, age-specific area-specific regulatory networks underlying neural differentiation. Moreover, combining single-cell profiling, progenitor purification lineage-tracing experiments, have untangled lineage relationships among subtypes during neurogenesis-to-gliogenesis transition. We identified tripotential intermediate subtype—tripotential cells (Tri-IPCs)—that responsible for local production GABAergic neurons, oligodendrocyte precursor astrocytes. Notably, most glioblastoma resemble Tri-IPCs at level, suggesting that cancer hijack processes enhance growth heterogeneity. Furthermore, integrating our with large-scale genome-wide association study data, created disease-risk map highlighting enriched risk associated autism spectrum disorder in second-trimester intratelencephalic neurons. Our sheds light molecular dynamics developing neocortex. Tripotential are astrocytes

Язык: Английский

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Challenges and opportunities to computationally deconvolve heterogeneous tissue with varying cell sizes using single-cell RNA-sequencing datasets

Genome biology, Год журнала: 2023, Номер 24(1)

Опубликована: Дек. 14, 2023

Abstract Deconvolution of cell mixtures in “bulk” transcriptomic samples from homogenate human tissue is important for understanding disease pathologies. However, several experimental and computational challenges impede transcriptomics-based deconvolution approaches using single-cell/nucleus RNA-seq reference atlases. Cells the brain blood have substantially different sizes, total mRNA, transcriptional activities, existing may quantify mRNA instead type proportions. Further, standards are lacking use atlases integrative analyses single-cell spatial transcriptomics data. We discuss how to approach these key with orthogonal “gold standard” datasets evaluating methods.

Язык: Английский

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Schizophrenia genomics: genetic complexity and functional insights

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(9), С. 611 - 624

Опубликована: Июль 19, 2024

Язык: Английский

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Molecular and cellular dynamics of the developing human neocortex at single-cell resolution

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 16, 2024

The development of the human neocortex is a highly dynamic process and involves complex cellular trajectories controlled by cell-type-specific gene regulation1. Here, we collected paired single-nucleus chromatin accessibility transcriptome data from 38 neocortical samples encompassing both prefrontal cortex primary visual cortex. These span five main developmental stages, ranging first trimester to adolescence. In parallel, performed spatial transcriptomic analysis on subset illustrate organization intercellular communication. This atlas enables us catalog cell type-, age-, area-specific regulatory networks underlying neural differentiation. Moreover, combining single-cell profiling, progenitor purification, lineage-tracing experiments, have untangled lineage relationships among subtypes during transition neurogenesis gliogenesis in neocortex. We identified tripotential intermediate subtype, termed Tri-IPC, responsible for local production GABAergic neurons, oligodendrocyte precursor cells, astrocytes. Remarkably, most glioblastoma cells resemble Tri-IPCs at level, suggesting that cancer hijack processes enhance growth heterogeneity. Furthermore, integrating our with large-scale GWAS data, created disease-risk map highlighting enriched ASD risk second-trimester intratelencephalic projection neurons. Our study sheds light landscape dynamics developing

Язык: Английский

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The cell-type underpinnings of the human functional cortical connectome

Nature Neuroscience, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 21, 2024

Язык: Английский

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Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases

Translational Psychiatry, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 25, 2025

Advancements in single-cell multimodal techniques have greatly enhanced our understanding of disease-relevant loci identified through genome-wide association studies (GWASs). To investigate the biological connections between eye and brain, we integrated bulk multiomic profiles with GWAS summary statistics for eight neuropsychiatric five ocular diseases. Our analysis uncovered latent factors explaining 61.7% genetic variance across these 13 diseases, revealing diverse correlational patterns among them. We 45 pleiotropic 91 candidate genes that contribute to disease risk. By integrating profiles, implicated excitatory neurons microglia as key contributors eye-brain connections. Polygenic enrichment further 15 regulons 16 were linked comorbid conditions. Functionally, neuron-specific involved axon guidance synaptic activity, while microglia-specific associated immune response cell activation. In sum, findings underscore link psychiatric disorders

Язык: Английский

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Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 19, 2025

Abstract Whole genome sequencing has identified over a billion non-coding variants in humans, while GWAS revealed the as significant contributor to disease. However, prioritizing causal common and rare human disease, understanding how selective pressures have shaped genome, remains challenge. Here, we predicted effects of 15 million with deep learning models trained on single-cell ATAC-seq across 132 cellular contexts adult fetal brain heart, producing nearly two context-specific predictions. Using these predictions, distinguish candidate underlying traits diseases their effects. While variant are more cell-type-specific, exert cell-type-shared regulatory effects, particularly targeting affecting neurons. To prioritize de novo mutations extreme developed FLARE, functional genomic model constraint. FLARE outperformed other methods case from autism-affected families near syndromic autism-associated genes; for example, identifying mutation outliers CNTNAP2 that would be missed by alternative approaches. Overall, our findings demonstrate potential integrating maps population genetics learning-based effect prediction elucidate mechanisms development disease–ultimately, supporting notion genetic contributions neurodevelopmental disorders predominantly rare.

Язык: Английский

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Integrated analysis of molecular atlases unveils modules driving developmental cell subtype specification in the human cortex

Nature Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Апрель 21, 2025

Human brain development requires generating diverse cell types, a process explored by single-cell transcriptomics. Through parallel meta-analyses of the human cortex in (seven datasets) and adulthood (16 datasets), we generated over 500 gene co-expression networks that can describe mechanisms cortical development, centering on peak stages neurogenesis. These meta-modules show dynamic subtype specificities throughout with several developmental displaying spatiotemporal expression patterns allude to potential roles fate specification. We validated these modules primary tissues. include meta-module 20, module elevated FEZF2+ deep layer neurons includes TSHZ3, transcription factor associated neurodevelopmental disorders. chimeroid experiments both FEZF2 TSHZ3 are required drive 20 activity neuron specification but through distinct modalities. studies demonstrate how meta-atlases engender further mechanistic analyses

Язык: Английский

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