The development of the human neocortex is highly dynamic, involving complex cellular trajectories controlled by gene regulation. Here we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and the primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence.
View Article and Find Full Text PDFDiverse retinal ganglion cells (RGCs) transmit distinct visual features from the eye to the brain. Recent studies have categorized RGCs into 45 types in mice based on transcriptomic profiles, showing strong alignment with morphological and electrophysiological properties. However, little is known about how these types are spatially arranged on the two-dimensional retinal surface-an organization that influences visual encoding-and how their local microenvironments impact development and neurodegenerative responses.
View Article and Find Full Text PDFAs the field of neural organoids and assembloids expands, there is an emergent need for guidance and advice on designing, conducting and reporting experiments to increase the reproducibility and utility of these models. In this Perspective, we present a framework for the experimental process that encompasses ensuring the quality and integrity of human pluripotent stem cells, characterizing and manipulating neural cells in vitro, transplantation techniques and considerations for modelling human development, evolution and disease. As with all scientific endeavours, we advocate for rigorous experimental designs tailored to explicit scientific questions as well as transparent methodologies and data sharing to provide useful knowledge for current research practices and for developing regulatory standards.
View Article and Find Full Text PDFThe Human Cell Atlas (HCA) is a global partnership "to create comprehensive reference maps of all human cells-the fundamental units of life - as a basis for both understanding human health and diagnosing, monitoring, and treating disease." ( https://www.humancellatlas.
View Article and Find Full Text PDFThe ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains.
View Article and Find Full Text PDFThe development of the human neocortex is a highly dynamic process and involves complex cellular trajectories controlled by cell-type-specific gene regulation. Here, we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence.
View Article and Find Full Text PDFThe nuclear genome is spatially organized into a three-dimensional (3D) architecture by physical association of large chromosomal domains with subnuclear compartments including the nuclear lamina at the radial periphery and nuclear speckles within the nucleoplasm. However, how spatial genome architecture regulates human brain development has been overlooked owing to technical limitations. Here, we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from midgestational human cortex, uncovering an intimate association between subnuclear genome compartmentalization, chromatin state and transcription.
View Article and Find Full Text PDFThe ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains.
View Article and Find Full Text PDFThe vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet.
View Article and Find Full Text PDFDuring development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons.
View Article and Find Full Text PDFThe temporal lobe of the human brain contains the entorhinal cortex (EC). This region of the brain is a highly interconnected integrative hub for sensory and spatial information; it also has a key role in episodic memory formation and is the main source of cortical hippocampal inputs. The human EC continues to develop during childhood, but neurogenesis and neuronal migration to the EC are widely considered to be complete by birth.
View Article and Find Full Text PDFThe development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. To address this, we integrated transcriptomic data from 241,096 cells (126,840 newly generated) in the prenatal and adult human hypothalamus to reveal a temporal trajectory from proliferative stem cell populations to mature hypothalamic cell types. Iterative clustering of the adult neurons identified 108 robust transcriptionally distinct neuronal subtypes representing 10 hypothalamic nuclei.
View Article and Find Full Text PDFMesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic options such as brain tissue-destructive surgery. Here, we report the development and characterization of a cell therapy alternative for drug-resistant MTLE, which is derived from a human embryonic stem cell line and comprises cryopreserved, post-mitotic, medial ganglionic eminence (MGE) pallial-type GABAergic interneurons.
View Article and Find Full Text PDFDuplication 15q (dup15q) syndrome is the most common genetic cause of autism spectrum disorder (ASD). Due to a higher genetic and phenotypic homogeneity compared to idiopathic autism, dup15q syndrome provides a well-defined setting to investigate ASD mechanisms. Previous bulk gene expression studies identified shared molecular changes in ASD.
View Article and Find Full Text PDFThe molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways.
View Article and Find Full Text PDFRadial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear.
View Article and Find Full Text PDFRadial glial cells, the stem cells of the cerebral cortex, extend a long basal fiber that ends in basal endfeet. A new study in PLOS Biology found that non-muscle myosins control basal endfoot integrity to regulate interneuron organization.
View Article and Find Full Text PDFUsing machine learning (ML), we interrogated the function of all human-chimpanzee variants in 2,645 human accelerated regions (HARs), finding 43% of HARs have variants with large opposing effects on chromatin state and 14% on neurodevelopmental enhancer activity. This pattern, consistent with compensatory evolution, was confirmed using massively parallel reporter assays in chimpanzee and human neural progenitor cells. The species-specific enhancer activity of HARs was accurately predicted from the presence and absence of transcription factor footprints in each species.
View Article and Find Full Text PDFMutations in the human progranulin (GRN) gene are a leading cause of frontotemporal lobar degeneration (FTLD). While previous studies implicate aberrant microglial activation as a disease-driving factor in neurodegeneration in the thalamocortical circuit in Grn-/- mice, the exact mechanism for neurodegeneration in FTLD-GRN remains unclear. By performing comparative single-cell transcriptomics in the thalamus and frontal cortex of Grn-/- mice and patients with FTLD-GRN, we have uncovered a highly conserved astroglial pathology characterized by upregulation of gap junction protein GJA1, water channel AQP4, and lipid-binding protein APOE, and downregulation of glutamate transporter SLC1A2 that promoted profound synaptic degeneration across the two species.
View Article and Find Full Text PDFNat Rev Neurosci
December 2022
Apical-basal progenitor cell polarity establishes key features of the radial and laminar architecture of the developing human cortex. The unique diversity of cortical stem cell populations and an expansion of progenitor population size in the human cortex have been mirrored by an increase in the complexity of cellular processes that regulate stem cell morphology and behaviour, including their polarity. The study of human cells in primary tissue samples and human stem cell-derived model systems (such as cortical organoids) has provided insight into these processes, revealing that protein complexes regulate progenitor polarity by controlling cell membrane adherence within appropriate cortical niches and are themselves regulated by cytoskeletal proteins, signalling molecules and receptors, and cellular organelles.
View Article and Find Full Text PDFInteractions between angiogenesis and neurogenesis regulate embryonic brain development. However, a comprehensive understanding of the stages of vascular cell maturation is lacking, especially in the prenatal human brain. Using fluorescence-activated cell sorting, single-cell transcriptomics, and histological and ultrastructural analyses, we show that an ensemble of endothelial and mural cell subtypes tile the brain vasculature during the second trimester.
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