Gene regulatory landscape of cerebral cortex folding DOI Creative Commons
Aditi Singh, Lucia Del-Valle-Anton, Camino de Juan Romero

и другие.

Science Advances, Год журнала: 2024, Номер 10(23)

Опубликована: Июнь 5, 2024

Folding of the cerebral cortex is a key aspect mammalian brain development and evolution, defects are linked to severe neurological disorders. Primary folding occurs in highly stereotyped patterns that predefined cortical germinal zones by transcriptomic protomap. The gene regulatory landscape governing emergence this protomap remains unknown. We characterized spatiotemporal dynamics expression active epigenetic (H3K27ac) across prospective folds fissures ferret. Our results show begins emerge at early embryonic stages, it involves cell-fate signaling pathways. H3K27ac reveals developmental restriction engages known regulators, including transcription factor Cux2 . Manipulating progenitors changed their proliferation pattern ferret, caused selective transcriptional changes as revealed single-cell RNA sequencing analyses. findings highlight relevance mechanisms defining folding.

Язык: Английский

Inferring and perturbing cell fate regulomes in human brain organoids DOI Creative Commons
Jonas Simon Fleck, Sophie Jansen, Damian Wollny

и другие.

Nature, Год журнала: 2022, Номер 621(7978), С. 365 - 372

Опубликована: Окт. 5, 2022

Self-organizing neural organoids grown from pluripotent stem cells

Язык: Английский

Процитировано

187
Single-cell brain organoid screening identifies developmental defects in autism DOI Creative Commons
Chong Li, Jonas Simon Fleck, Catarina Martins‐Costa

и другие.

Nature, Год журнала: 2023, Номер 621(7978), С. 373 - 380

Опубликована: Сен. 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.

Язык: Английский

Процитировано

131
Genetics of human brain development DOI
Yi Zhou, Hongjun Song, Guo‐li Ming

и другие.

Nature Reviews Genetics, Год журнала: 2023, Номер 25(1), С. 26 - 45

Опубликована: Июль 28, 2023

Язык: Английский

Процитировано

74
Massively parallel in vivo Perturb-seq reveals cell-type-specific transcriptional networks in cortical development DOI Creative Commons

Xinhe Zheng,

Boli Wu,

Yuejia Liu

и другие.

Cell, Год журнала: 2024, Номер 187(13), С. 3236 - 3248.e21

Опубликована: Май 20, 2024

Leveraging AAVs' versatile tropism and labeling capacity, we expanded the scale of in vivo CRISPR screening with single-cell transcriptomic phenotyping across embryonic to adult brains peripheral nervous systems. Through extensive tests 86 vectors AAV serotypes combined a transposon system, substantially amplified efficacy accelerated gene delivery from weeks days. Our proof-of-principle utero screen identified pleiotropic effects Foxg1, highlighting its tight regulation distinct networks essential for cell fate specification Layer 6 corticothalamic neurons. Notably, our platform can label >6% cerebral cells, surpassing current state-of-the-art at <0.1% by lentivirus, achieve analysis over 30,000 cells one experiment enable massively parallel Perturb-seq. Compatible various phenotypic measurements (single-cell or spatial multi-omics), it presents flexible approach interrogate function types vivo, translating variants their causal function.

Язык: Английский

Процитировано

28
Cellular and Molecular Mechanisms Linking Human Cortical Development and Evolution DOI
Baptiste Libé‐Philippot, Pierre Vanderhaeghen

Annual Review of Genetics, Год журнала: 2021, Номер 55(1), С. 555 - 581

Опубликована: Сен. 18, 2021

The cerebral cortex is at the core of brain functions that are thought to be particularly developed in human species. Human specificities stem from divergent features corticogenesis, leading increased cortical size and complexity. Underlying cellular mechanisms include prolonged patterns neuronal generation maturation, as well amplification specific types stem/progenitor cells. While gene regulatory networks corticogenesis appear largely conserved among all mammals including humans, they have evolved primates, species, through emergence rapidly transcriptional elements, recently duplicated novel genes. These human-specific molecular together control key milestones often affected neurodevelopmental disorders, thus linking neural development, evolution, diseases.

Язык: Английский

Процитировано

57
Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders DOI Creative Commons
Jordy Dekker, Rachel Schot, Michiel Bongaerts

и другие.

The American Journal of Human Genetics, Год журнала: 2023, Номер 110(2), С. 251 - 272

Опубликована: Янв. 19, 2023

Язык: Английский

Процитировано

32
SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo DOI Creative Commons
Ben Vermaercke, Ryohei Iwata, Keimpe Wierda

и другие.

Neuron, Год журнала: 2024, Номер 112(18), С. 3058 - 3068.e8

Опубликована: Авг. 6, 2024

Human brain ontogeny is characterized by a considerably prolonged neotenic development of cortical neurons and circuits. Neoteny thought to be essential for the acquisition advanced cognitive functions, which are typically altered in intellectual disability (ID) autism spectrum disorders (ASDs). neuronal neoteny could disrupted some forms ID and/or ASDs, but this has never been tested. Here, we use xenotransplantation human into mouse model SYNGAP1 haploinsufficiency, one most prevalent genetic causes ID/ASDs. We find that SYNGAP1-deficient display strong acceleration morphological functional synaptic formation maturation alongside plasticity. At circuit level, SYNGAP1-haploinsufficient precocious responsiveness visual stimulation months ahead time. Our findings indicate required cell autonomously neoteny, providing novel links between human-specific developmental mechanisms

Язык: Английский

Процитировано

12
A human-specific, concerted repression of microcephaly genes contributes to radiation-induced growth defects in cortical organoids DOI Creative Commons
Jéssica Honorato Ribeiro,

Emre Etlioglu,

Jasmine Buset

и другие.

iScience, Год журнала: 2025, Номер 28(2), С. 111853 - 111853

Опубликована: Янв. 21, 2025

Язык: Английский

Процитировано

2
Folding brains: from development to disease modeling DOI
Lucia Del-Valle-Anton, Vı́ctor Borrell

Physiological Reviews, Год журнала: 2021, Номер 102(2), С. 511 - 550

Опубликована: Окт. 11, 2021

The human brain is characterized by the large size and intricate folding of its cerebral cortex, which are fundamental for our higher cognitive function frequently altered in pathological dysfunction. Cortex not unique to humans, nor even primates, but common across mammals. Cortical growth result complex developmental processes that involve neural stem progenitor cells their cellular lineages, migration differentiation neurons, genetic programs regulate fine-tune these processes. All factors combined generate mechanical stress strain on developing tissue, ultimately drives orderly cortical deformation folding. In this review we examine summarize current knowledge molecular, cellular, histogenic, mechanisms involved influence how they emerged changed during mammalian evolution. We discuss main types malformations cortex folding, specific origin, investigating causes has illuminated understanding key events involved. close presenting animal vitro models currently used study devastating disorders children, what challenges remain ahead us fully understand

Язык: Английский

Процитировано

47
FASN-dependent de novo lipogenesis is required for brain development DOI Creative Commons
Daniel Gonzalez-Bohorquez, Isabel M. Gallego López, Baptiste N. Jaeger

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(2)

Опубликована: Янв. 7, 2022

Significance Regulation of cellular metabolism in proliferating progenitor cells and their neuronal progeny is critical for brain development function. Here, we identify a pivotal role fatty acid synthase (FASN)-dependent de novo lipogenesis mouse human development, as genetic deletion FASN leads to microcephaly the developing cortex cortical malformations embryonic stem cell–derived forebrain organoids. Mechanistically, show that required proper polarity apical cells. The dual approach applied here, using genetics organoids, establishes FASN-dependent identifies link between progenitor-cell lipid metabolism.

Язык: Английский

Процитировано

31