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Enhanced cortical neural stem cell identity through SMAD/WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

ABSTRACT: Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early dual-SMAD/WNT inhibition course is necessary and sufficient for establishing robust and lasting cortical organoid NSC identity, efficiently suppressing of non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC specification capacity. Accordingly, this method selectively enriches for outer radial glia (oRG) NSCs, which cytoarchitecturally demarcate well-defined outer sub-ventricular (oSVZ)-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD/WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring fundamental molecular and cytoarchitectural features of cortical development and meaningful disease modeling.

PROVIDER: EGAS00001006063 | EGA |

REPOSITORIES: EGA

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Enhanced cortical neural stem cell identity through short SMAD/WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells.

Project description:Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity under a variety of derivation methods, suggesting inadequate patterning of early neural stem cell (NSC) starting populations. Here we show that a short combined Dual SMAD/WNT inhibition course during early organoid establishment is sufficient for yielding robust and lasting cortical identity with efficient suppression of non-cortical fates in organoid NSCs. In contrast, other widely used methods are inconsistent in their cortical specification capacity. Furthermore, combined inhibition selectively enriches for outer radial glia (oRG) cells in organoids that demarcate well-defined outer sub-ventricular (oSVZ)-like regions. Finally, combined inhibition enables superior NSC radial organization, further facilitates the generation of molecularly distinct deep and upper cortical layer neurons, and uncovers cortex-specific microcephaly defects. Thus, combined inhibition is critical for establishing a rich cortical cell repertoire, for enabling fundamental cytoarchitectural features of cortical development, and for meaningful disease modeling.

2022-03-16 | GSE189981 | GEO

Enhanced cortical neural stem cell identity through short SMAD/WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells.

Project description:Enhanced cortical neural stem cell identity through short SMAD/WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells.

| PRJNA785455 | ENA

Single cell RNAseq analysis revealed long-lasting adverse effects of prenatal tamoxifen administration on neurogenesis

Project description:We report that administration of tamoxifen (TAM) during early stages of cortical neurogenesis promoted precocious neural differentiation, while it inhibited neural progenitor cell (NPC) proliferation. The TAM-induced inhibition of NPC proliferation led to deficits in cortical neurogenesis, dendritic morphogenesis, synaptic formation, and cortical patterning in neonatal and postnatal offspring. Mechanistically, by employing single cell RNA sequencing (scRNA-seq) analysis combined with in vivo and in vitro assays, we showed TAM could exert these drastic effects mainly through dysregulating Wnt-Dmrta2 signaling pathway.

2020-06-10 | GSE152125 | GEO

Epigenetic regulation by BAF (mSWI/SNF) complexes limits neural stem cell proliferation by suppressing Wnt signaling in late cortical neurogenesis

Project description:Epigenetic regulation by BAF (mSWI/SNF) complexes limits neural stem cell proliferation by suppressing Wnt signaling in late cortical neurogenesis

| PRJNA417717 | ENA

Transcriptome analysis of mouse cerebral cortical neural progenitor cells

Project description:Transcriptome analysis of neural progenitor/stem cells is limited by the lack of a reliable method for cell isolation. We have designed a genetic dual reporter strategy that can allow prospective isolation of cortical neural progenitor cells and their neuronal progeny form the same animals. These cells should be a good cell source for comparative global analysis. Cortical neural progenitor cells and their neuronal progeny were purified using a dual reporter strategy. The purified cells were used for comparative expression profiling.

2011-09-19 | E-GEOD-22946 | biostudies-arrayexpress

Rack1 is Essential for Corticogenesis by Preventing P21-Dependent Senescence in Neural Stem Cells

Project description:Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation and survival. Disruptions lead to neurodevelopmental disorders including microcephaly. Here, we implicate the inhibition of NSC senescence as a mechanism underlying neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs. Deletion of Rack1 in developing cortical progenitors leads to a microcephaly phenotype. Strikingly, the absence of Rack1 decreases neurogenesis and promotes a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway is dramatically activated in Rack1-null NSCs, and removal of p21 significantly rescues the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of TGF-β/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of p21-induced NSC senescence as a critical mechanism behind normal cortical development.

2021-08-09 | PXD027798 |

Sliced Human Cortical Organoids for Modeling Distinct Cortical Neuronal Layer Formation

Project description:Brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture representative of late developmental stages. Here, we establish the sliced neocortical organoid (SNO) system, which bypasses the diffusion limit to prevent cell death and sustains neurogenesis in organized neural progenitor zones throughout long-term cultures. This method leads to the formation of an expanded cortical plate that establishes distinct upper and deep cortical layers, resembling the third-trimester human neocortex. Using the SNO system, we further identify a critical role of WNT/β-Catenin signaling in regulating cortical neuron fate specification, which is disrupted by a psychiatric disorder-associated genetic mutation in patient iPSC-derived organoids. These results demonstrate the utility of SNOs as a model for investigating previously inaccessible human-specific late-stage cortical developmental and disease-relevant mechanisms

2020-03-05 | GSE137941 | GEO

Gastruloids generated without exogenous Wnt activation develop anterior neural tissues [EmbryoidsTruseq2]

Project description:Here we describe an approach to generate gastruloids that have a more complete antero-posterior development. We used bioengineered hydrogel microwell arrays to promote the robust derivation of mouse ESCs into post-implantation epiblast-like (EPI) aggregates in a reproducible and scalable manner. These EPI aggregates break symmetry and axially elongate without external chemical stimulation. Inhibition of WNT signaling in early stages of development leads to the formation of gastruloids with anterior neural tissues.

2021-04-12 | GSE171210 | GEO

DOT1L protects neural stem cells from ER stress

Project description:In order to understand the role of H3K79me2 and DOT1L during CNS development, we analysed neural stem cells after pharmacological inhibition of DOT1L (5 µM SGC0946). To identify target genes of DOT1L in the cortex, we determined the transcriptome of cortical progenitor cells derived from E14.5 NMRI mice after interference with DOT1L activity for three days in vitro (DIV3). Therefore, three independent experiments were performed (ctrl1 – inh1, ctrl2 – inh2, ctrl3 – inh3).

2015-12-31 | E-MTAB-3521 | biostudies-arrayexpress

Comparative transcriptome analysis of the regenerating zebrafish telencephalon unravels a key regulatory role for Wnt/β-catenin signaling at the early wound healing stage

Project description:Adult zebrafish can completely regenerate a wide range of injured organs including the CNS. RNA sequencing (RNA-Seq) is a high-throughput sequencing method facilitating quantification of gene expression in a precisely manner. Development of RNA-Seq technologies and their extensive data-analysis methods make investigation of regulatory genes and functional gene annotations possible under specific conditions. In this study, we reveal the whole transcriptome profiles of both the lesioned and unlesioned hemispheres of the zebrafish telencephalon at early wound healing (20 hour post lesion) and early proliferative (3 day post lesion) stages of regeneration. Moreover, we uncover Wnt/β-catenin signaling as a key pathway that is activated at the early wound healing stage.

2020-10-05 | E-MTAB-9321 | biostudies-arrayexpress

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