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- Callaway, EM, et al.
(författare)
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A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
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Tidskriftsartikel (refereegranskat)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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- Zang, ZL, et al.
(författare)
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Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids
- 2022
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Ingår i: Frontiers in molecular neuroscience. - : Frontiers Media SA. - 1662-5099. ; 15, s. 1023765-
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Tidskriftsartikel (refereegranskat)abstract
- Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/β-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain.
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