Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder DOI Creative Commons

Lucia Fernandez Cardo,

Daniel Cabezas de la Fuente, Meng Li

et al.

Molecular Autism, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 20, 2023

Abstract Background Disruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech motor delays. Despite the association neurodevelopmental disorders, little is known about its role in brain development. Methods Using CRISPR/Cas9 genome editing technology, we generated a model human embryonic stem cells (hESCs) examined effects SETBP1-deficiency neural progenitors (NPCs) neurons derived from these using battery cellular assays, genome-wide transcriptomic profiling drug-based phenotypic rescue. Results Neural induction occurred efficiently all models as indicated uniform transition into rosettes. However, SETBP1-deficient NPCs exhibited an extended proliferative window decrease neurogenesis coupled deficiency their ability acquire ventral forebrain fate. Genome-wide transcriptome biochemical analysis revealed enhanced activation Wnt/ β -catenin signaling deleted cells. Crucially, treatment small molecule Wnt inhibitor XAV939 restored hyper canonical activity both cortical MGE neuronal differentiation. Limitations The current study based isogenic hESC lines genome-edited further studies would benefit use patient-derived iPSC that may harbor additional genetic risk aggravate pathology Conclusions We identified important for controlling progenitor expansion neurogenic Our establishes novel regulatory link between during provides mechanistic insights structural abnormalities potential therapeutic avenues

Language: Английский

Human cerebral organoids — a new tool for clinical neurology research DOI Open Access
Oliver L. Eichmüller, Juergen A. Knoblich

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 18(11), P. 661 - 680

Published: Oct. 17, 2022

Language: Английский

Citations

174
Molecular and cellular evolution of the primate dorsolateral prefrontal cortex DOI
Shaojie Ma, Mario Škarica, Qian Li

et al.

Science, Journal Year: 2022, Volume and Issue: 377(6614)

Published: Aug. 25, 2022

The granular dorsolateral prefrontal cortex (dlPFC) is an evolutionary specialization of primates that centrally involved in cognition. We assessed more than 600,000 single-nucleus transcriptomes from adult human, chimpanzee, macaque, and marmoset dlPFC. Although most cell subtypes defined transcriptomically are conserved, we detected several exist only a subset species as well substantial species-specific molecular differences across homologous neuronal, glial, non-neural subtypes. latter exemplified by human-specific switching between expression the neuropeptide somatostatin tyrosine hydroxylase, rate-limiting enzyme dopamine production certain interneurons. above also illustrated neuropsychiatric risk gene

Language: Английский

Citations

156
Single-cell brain organoid screening identifies developmental defects in autism DOI Creative Commons
Chong Li, Jonas Simon Fleck, Catarina Martins‐Costa

et al.

Nature, Journal Year: 2023, Volume and Issue: 621(7978), P. 373 - 380

Published: Sept. 13, 2023

Abstract The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders 1–4 . Cerebral organoids enable study a context. We have developed CRISPR–human organoids–single-cell RNA sequencing (CHOOSE) system, which uses verified pairs guide RNAs, inducible CRISPR–Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening mosaic organoids. Here we show perturbation 36 high-risk autism spectrum disorder genes related transcriptional regulation uncovers their effects on cell fate determination. find dorsal intermediate progenitors, ventral progenitors upper-layer excitatory neurons are among most vulnerable types. construct developmental gene regulatory network cerebral from transcriptomes chromatin modalities identify disorder-associated perturbation-enriched modules. Perturbing members BRG1/BRM-associated factor (BAF) remodelling complex leads enrichment telencephalon progenitors. Specifically, mutating BAF subunit ARID1B affects transition oligodendrocyte interneuron precursor cells, phenotype confirmed patient-specific induced pluripotent stem cell-derived Our paves way high-throughput phenotypic characterization disease susceptibility organoid models with state, molecular pathway readouts.

Language: Английский

Citations

129
Comprehensive cell atlas of the first-trimester developing human brain DOI
Emelie Braun, Miri Danan-Gotthold, Lars E. Borm

et al.

Science, Journal Year: 2023, Volume and Issue: 382(6667)

Published: Oct. 12, 2023

The adult human brain comprises more than a thousand distinct neuronal and glial cell types, diversity that emerges during early development. To reveal the precise sequence of events development, we used single-cell RNA sequencing spatial transcriptomics uncovered states trajectories in brains at 5 to 14 postconceptional weeks (pcw). We identified 12 major classes are organized as ~600 states, which map anatomical domains pcw. described detailed differentiation forebrain midbrain found large number region-specific glioblasts mature into pre-astrocytes pre-oligodendrocyte precursor cells. Our findings establishment types first trimester

Language: Английский

Citations

107
Ductile and ultrahigh-strength eutectic high-entropy alloys by large-volume 3D printing DOI
Yiping Lu, Xiaoxiang Wu, Zhenghong Fu

et al.

Journal of Material Science and Technology, Journal Year: 2022, Volume and Issue: 126, P. 15 - 21

Published: April 20, 2022

Language: Английский

Citations

87
Genetics of human brain development DOI
Yi Zhou, Hongjun Song, Guo‐li Ming

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 25(1), P. 26 - 45

Published: July 28, 2023

Language: Английский

Citations

72
The single-cell and spatial transcriptional landscape of human gastrulation and early brain development DOI Creative Commons
Bo Zeng, Zeyuan Liu,

Yufeng Lu

et al.

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(6), P. 851 - 866.e7

Published: May 15, 2023

The emergence of the three germ layers and lineage-specific precursor cells orchestrating organogenesis represent fundamental milestones during early embryonic development. We analyzed transcriptional profiles over 400,000 from 14 human samples collected post-conceptional weeks (PCW) 3 to 12 delineate dynamic molecular cellular landscape gastrulation nervous system described diversification cell types, spatial patterning neural tube cells, signaling pathways likely involved in transforming epiblast into neuroepithelial then radial glia. resolved 24 clusters glial along outlined differentiation trajectories for main classes neurons. Lastly, we identified conserved distinctive features across species by comparing single-cell transcriptomic between humans mice. This comprehensive atlas sheds light on mechanisms underlying brain

Language: Английский

Citations

57
Spatiotemporal transcriptome atlas reveals the regional specification of the developing human brain DOI Creative Commons
Yanxin Li, Zhong‐Qiu Li, Changliang Wang

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(26), P. 5892 - 5909.e22

Published: Dec. 1, 2023

Language: Английский

Citations

44
Human fetal brain self-organizes into long-term expanding organoids DOI Creative Commons
Delilah Hendriks, Anna Pagliaro, Francesco Andreatta

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(3), P. 712 - 732.e38

Published: Jan. 8, 2024

Human brain development involves an orchestrated, massive neural progenitor expansion while a multi-cellular tissue architecture is established. Continuously expanding organoids can be grown directly from multiple somatic tissues, yet to date, solely established pluripotent stem cells. Here, we show that healthy human fetal in vitro self-organizes into (FeBOs), phenocopying aspects of vivo cellular heterogeneity and complex organization. FeBOs expanded over long time periods. FeBO growth requires maintenance integrity, which ensures production tissue-like extracellular matrix (ECM) niche, ultimately endowing expansion. lines derived different areas the central nervous system (CNS), including dorsal ventral forebrain, preserve their regional identity allow probe positional identity. Using CRISPR-Cas9, showcase generation syngeneic mutant for study cancer. Taken together, constitute complementary CNS organoid platform.

Language: Английский

Citations

40
Molecular and cellular dynamics of the developing human neocortex DOI Creative Commons
Li Wang, Cheng Wang, Juan Moriano

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 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

Language: Английский

Citations

7