27 results on '"Kriegstein, Arnold R."'
Search Results
2. Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells
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Bershteyn, Marina, Hayashi, Yohei, Desachy, Guillaume, Hsiao, Edward C., Sami, Salma, Tsang, Kathryn M., Weiss, Lauren A., Kriegstein, Arnold R., Yamanaka, Shinya, and Wynshaw-Boris, Anthony
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Stem cells -- Physiological aspects -- Research ,Chromosomes -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation (1,2). Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions (2). Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate (3-9). The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) (10-12) from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-derived iPSCs devoid of the original chromosomal aberration. Our results suggest a fundamentally different function for cellular reprogramming as a means of 'chromosome therapy' (13) to reverse combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. In addition, our work provides an experimentally tractable human cellular system for studying mechanisms of chromosomal number control, which is of critical relevance to human development and disease., We obtained fibroblasts from a Miller Dieker Syndrome (MDS) patient with ring chromosome 17, subsequently referred to as r(17). MDS is caused by heterozygous deletions of human band 17p13.3 (refs [...]
- Published
- 2014
3. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults
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Sorrells, Shawn F., Paredes, Mercedes F., Cebrian-Silla, Arantxa, Sandoval, Kadellyn, Qi, Dashi, Kelley, Kevin W., James, David, Mayer, Simone, Chang, Julia, Auguste, Kurtis I., Chang, Edward F., Gutierrez, Antonio J., Kriegstein, Arnold R., Mathern, Gary W., Oldham, Michael C., Huang, Eric J., Garcia-Verdugo, Jose Manuel, Yang, Zhengang, and Alvarez-Buylla, Arturo
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Rhesus monkey -- Physiological aspects -- Observations ,Neurogenesis -- Observations ,Hippocampus (Brain) -- Observations ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Shawn F. Sorrells [1, 2]; Mercedes F. Paredes [1, 3]; Arantxa Cebrian-Silla [4]; Kadellyn Sandoval [1, 3]; Dashi Qi [5]; Kevin W. Kelley [1]; David James [1]; Simone Mayer [...]
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- 2018
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4. Developmental genetics of vertebrate glial-cell specification
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Rowitch, David H. and Kriegstein, Arnold R.
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Neurons -- Physiological aspects ,Vertebrates -- Physiological aspects ,Nervous system diseases -- Genetic aspects ,Astrocytes -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Oligodendrocytes and astrocytes are macroglial cells of the vertebrate central nervous system. These cells have diverse roles in the maintenance of neurological function. In the embryo, the genetic mechanisms that underlie the specification of macroglial precursors in vivo appear strikingly similar to those that regulate the development of the diverse neuron types. The switch from producing neuronal to glial subtype-specific precursors can be modelled as an interplay between region-restricted components and temporal regulators that determine neurogenic or gliogenic phases of development, contributing to glial diversity. Gaining insight into the developmental genetics of macroglia has great potential to improve our understanding of a variety of neurological disorders in humans., Glia make up 10-20% of the cells in the Drosophila nervous system and at least 50% of the cells in the human brain. These findings indicate that glial-cell function is [...]
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- 2010
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5. Neurogenic radial glia in the outer subventricular zone of human neocortex
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Hansen, David V., Lui, Jan H., Parker, Philip R.L., and Kriegstein, Arnold R.
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Stem cells -- Physiological aspects -- Research ,Cellular signal transduction -- Research ,Neocortex -- Physiological aspects -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Neurons in the developing rodent cortex are generated from radial glial cells that function as neural stem cells. These epithelial cells line the cerebral ventricles and generate intermediate progenitor cells that migrate into the subventricular zone (SVZ) and proliferate to increase neuronal number. The developing human SVZ has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. However, OSVZ progenitor cell types and their contribution to neurogenesis are not well understood. Here we show that large numbers of radial glia-like cells and intermediate progenitor cells populate the human OSVZ. We find that OSVZ radial glia-like cells have a long basal process but, surprisingly, are non-epithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, we demonstrate that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor cells that can proliferate further. We also show that inhibition of Notch signalling in OSVZ progenitor cells induces their neuronal differentiation. The establishment of non-ventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain., One of the most marked evolutionary changes underlying the unique cognitive abilities of humans is the greatly enlarged cerebral cortex. This change must be reflected in differences in progenitor cell [...]
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- 2010
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6. Gap junction adhesion is necessary for radial migration in the neocortex
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Elias, Laura A. B., Wang, Doris D., and Kriegstein, Arnold R.
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Laura A. B. Elias (corresponding author) [1, 2]; Doris D. Wang [1, 2]; Arnold R. Kriegstein (corresponding author) [2] During neocortical brain development, radial glia, which reside in the [...]
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- 2007
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7. Neurons derived from radial glial cells establish radial units in neocortex
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Noctor, Stephen C., Flint, Alexander C., Weissman, Tamily A., Dammerman, Ryan S., and Kriegstein, Arnold R.
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Stephen C. Noctor [1]; Alexander C. Flint [1]; Tamily A. Weissman [2]; Ryan S. Dammerman [2]; Arnold R. Kriegstein (corresponding author) [1, 2, 3] The neocortex of the adult [...]
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- 2001
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8. Cell reprogramming gets direct: in a feat of biological wizardry, one type of differentiated cell has been directly converted into another, completely distinct type. Notably, the approach does not require a stem-cell intermediate stage
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Nicholas, Cory R. and Kriegstein, Arnold R.
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Stem cells -- Physiological aspects -- Genetic aspects -- Research ,Genetic regulation -- Research ,Central nervous system diseases -- Care and treatment -- Genetic aspects -- Research ,Transcription factors -- Physiological aspects -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Barriers to transdifferentiation--the direct conversion or reprogramming of one cell type into another--are falling fast. On page 1035 of this issue, Vierbuchen et al. (1) maintain the pace of this [...]
- Published
- 2010
9. Protracted neuronal recruitment in the temporal lobes of young children.
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Nascimento MA, Biagiotti S, Herranz-Pérez V, Santiago S, Bueno R, Ye CJ, Abel TJ, Zhang Z, Rubio-Moll JS, Kriegstein AR, Yang Z, Garcia-Verdugo JM, Huang EJ, Alvarez-Buylla A, and Sorrells SF
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- Animals, Child, Preschool, Humans, Infant, Entorhinal Cortex cytology, Entorhinal Cortex physiology, Ganglionic Eminence cytology, Interneurons cytology, Interneurons physiology, Macaca mulatta, Single-Cell Gene Expression Analysis, Cell Movement, Neurons cytology, Neurons physiology, Temporal Lobe cytology, Temporal Lobe growth & development
- Abstract
The 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
1-4 . The human EC continues to develop during childhood5 , but neurogenesis and neuronal migration to the EC are widely considered to be complete by birth. Here we show that the human temporal lobe contains many young neurons migrating into the postnatal EC and adjacent regions, with a large tangential stream persisting until the age of around one year and radial dispersal continuing until around two to three years of age. By contrast, we found no equivalent postnatal migration in rhesus macaques (Macaca mulatta). Immunostaining and single-nucleus RNA sequencing of ganglionic eminence germinal zones, the EC stream and the postnatal EC revealed that most migrating cells in the EC stream are derived from the caudal ganglionic eminence and become LAMP5+ RELN+ inhibitory interneurons. These late-arriving interneurons could continue to shape the processing of sensory and spatial information well into postnatal life, when children are actively interacting with their environment. The EC is one of the first regions of the brain to be affected in Alzheimer's disease, and previous work has linked cognitive decline to the loss of LAMP5+ RELN+ cells6,7 . Our investigation reveals that many of these cells arrive in the EC through a major postnatal migratory stream in early childhood., (© 2023. The Author(s).)- Published
- 2024
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10. A cross-species proteomic map reveals neoteny of human synapse development.
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Wang L, Pang K, Zhou L, Cebrián-Silla A, González-Granero S, Wang S, Bi Q, White ML, Ho B, Li J, Li T, Perez Y, Huang EJ, Winkler EA, Paredes MF, Kovner R, Sestan N, Pollen AA, Liu P, Li J, Piao X, García-Verdugo JM, Alvarez-Buylla A, Liu Z, and Kriegstein AR
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- Adolescent, Animals, Child, Child, Preschool, Humans, Infant, Infant, Newborn, Mice, Young Adult, Cognition physiology, Dendritic Spines, Gestational Age, Macaca, Neurons metabolism, Post-Synaptic Density metabolism, Rho Guanine Nucleotide Exchange Factors metabolism, Signal Transduction, Species Specificity, Proteomics, Synapses metabolism, Synapses physiology
- Abstract
The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood
1,2 . 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. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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11. Zika virus alters centrosome organization to suppress the innate immune response.
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Kodani A, Knopp KA, Di Lullo E, Retallack H, Kriegstein AR, DeRisi JL, and Reiter JF
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- Animals, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Centrosome metabolism, Humans, Immunity, Innate, Microcephaly metabolism, Zika Virus physiology, Zika Virus Infection
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Zika virus (ZIKV) is a flavivirus transmitted via mosquitoes and sex to cause congenital neurodevelopmental defects, including microcephaly. Inherited forms of microcephaly (MCPH) are associated with disrupted centrosome organization. Similarly, we found that ZIKV infection disrupted centrosome organization. ZIKV infection disrupted the organization of centrosomal proteins including CEP63, a MCPH-associated protein. The ZIKV nonstructural protein NS3 bound CEP63, and expression of NS3 was sufficient to alter centrosome architecture and CEP63 localization. Loss of CEP63 suppressed ZIKV-induced centrosome disorganization, indicating that ZIKV requires CEP63 to disrupt centrosome organization. ZIKV infection or CEP63 loss decreased the centrosomal localization and stability of TANK-binding kinase 1 (TBK1), a regulator of the innate immune response. ZIKV infection also increased the centrosomal accumulation of the CEP63 interactor DTX4, a ubiquitin ligase that degrades TBK1. Therefore, we propose that ZIKV disrupts CEP63 function to increase centrosomal DTX4 localization and destabilization of TBK1, thereby tempering the innate immune response., (© 2022 The Authors.)
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- 2022
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12. A nomenclature consensus for nervous system organoids and assembloids.
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Pașca SP, Arlotta P, Bateup HS, Camp JG, Cappello S, Gage FH, Knoblich JA, Kriegstein AR, Lancaster MA, Ming GL, Muotri AR, Park IH, Reiner O, Song H, Studer L, Temple S, Testa G, Treutlein B, and Vaccarino FM
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- Humans, Models, Biological, Pluripotent Stem Cells cytology, Consensus, Nervous System cytology, Nervous System pathology, Organoids cytology, Organoids pathology, Terminology as Topic
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Self-organizing three-dimensional cellular models derived from human pluripotent stem cells or primary tissue have great potential to provide insights into how the human nervous system develops, what makes it unique and how disorders of the nervous system arise, progress and could be treated. Here, to facilitate progress and improve communication with the scientific community and the public, we clarify and provide a basic framework for the nomenclature of human multicellular models of nervous system development and disease, including organoids, assembloids and transplants., (© 2022. Springer Nature Limited.)
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- 2022
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13. An atlas of cortical arealization identifies dynamic molecular signatures.
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Bhaduri A, Sandoval-Espinosa C, Otero-Garcia M, Oh I, Yin R, Eze UC, Nowakowski TJ, and Kriegstein AR
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- Atlases as Topic, Base Sequence, Biomarkers metabolism, Humans, Neocortex metabolism, Neurogenesis, Neuroglia classification, Neuroglia cytology, Neuroglia metabolism, Neurons classification, Neurons cytology, Neurons metabolism, Reproducibility of Results, Single-Cell Analysis, Time Factors, Gene Expression Regulation, Developmental, Neocortex cytology, Neocortex embryology
- Abstract
The human brain is subdivided into distinct anatomical structures, including the neocortex, which in turn encompasses dozens of distinct specialized cortical areas. Early morphogenetic gradients are known to establish early brain regions and cortical areas, but how early patterns result in finer and more discrete spatial differences remains poorly understood
1 . Here we use single-cell RNA sequencing to profile ten major brain structures and six neocortical areas during peak neurogenesis and early gliogenesis. Within the neocortex, we find that early in the second trimester, a large number of genes are differentially expressed across distinct cortical areas in all cell types, including radial glia, the neural progenitors of the cortex. However, the abundance of areal transcriptomic signatures increases as radial glia differentiate into intermediate progenitor cells and ultimately give rise to excitatory neurons. Using an automated, multiplexed single-molecule fluorescent in situ hybridization approach, we find that laminar gene-expression patterns are highly dynamic across cortical regions. Together, our data suggest that early cortical areal patterning is defined by strong, mutually exclusive frontal and occipital gene-expression signatures, with resulting gradients giving rise to the specification of areas between these two poles throughout successive developmental timepoints., (© 2021. The Author(s).)- Published
- 2021
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14. Distinct nuclear compartment-associated genome architecture in the developing mammalian brain.
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Ahanger SH, Delgado RN, Gil E, Cole MA, Zhao J, Hong SJ, Kriegstein AR, Nowakowski TJ, Pollen AA, and Lim DA
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- Animals, Genetic Variation, Genome-Wide Association Study, Humans, Macaca, Mice, Mice, Inbred C57BL, Neural Stem Cells physiology, Schizophrenia genetics, Brain physiology, Cell Nucleus physiology, Gene Expression genetics, Genome genetics, Neurogenesis physiology
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Nuclear compartments are thought to play a role in three-dimensional genome organization and gene expression. In mammalian brain, the architecture and dynamics of nuclear compartment-associated genome organization is not known. In this study, we developed Genome Organization using CUT and RUN Technology (GO-CaRT) to map genomic interactions with two nuclear compartments-the nuclear lamina and nuclear speckles-from different regions of the developing mouse, macaque and human brain. Lamina-associated domain (LAD) architecture in cells in vivo is distinct from that of cultured cells, including major differences in LADs previously considered to be cell type invariant. In the mouse and human forebrain, dorsal and ventral neural precursor cells have differences in LAD architecture that correspond to their regional identity. LADs in the human and mouse cortex contain transcriptionally highly active sub-domains characterized by broad depletion of histone-3-lysine-9 dimethylation. Evolutionarily conserved LADs in human, macaque and mouse brain are enriched for transcriptionally active neural genes associated with synapse function. By integrating GO-CaRT maps with genome-wide association study data, we found speckle-associated domains to be enriched for schizophrenia risk loci, indicating a physical relationship between these disease-associated genetic variants and a specific nuclear structure. Our work provides a framework for understanding the relationship between distinct nuclear compartments and genome function in brain development and disease., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
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- 2021
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15. Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia.
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Eze UC, Bhaduri A, Haeussler M, Nowakowski TJ, and Kriegstein AR
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- Animals, Cerebral Cortex cytology, Humans, Single-Cell Analysis, Cerebral Cortex embryology, Ependymoglial Cells cytology, Neural Stem Cells cytology, Neuroepithelial Cells cytology, Neurogenesis
- Abstract
The human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.
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- 2021
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16. Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency.
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Zhang J, Velmeshev D, Hashimoto K, Huang YH, Hofmann JW, Shi X, Chen J, Leidal AM, Dishart JG, Cahill MK, Kelley KW, Liddelow SA, Seeley WW, Miller BL, Walther TC, Farese RV Jr, Taylor JP, Ullian EM, Huang B, Debnath J, Wittmann T, Kriegstein AR, and Huang EJ
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- Aging genetics, Aging pathology, Animals, Cell Nucleus genetics, Cell Nucleus pathology, Complement Activation drug effects, Complement Activation immunology, Complement C1q antagonists & inhibitors, Complement C1q immunology, Complement C3b antagonists & inhibitors, Complement C3b immunology, Culture Media, Conditioned chemistry, Culture Media, Conditioned pharmacology, DNA-Binding Proteins metabolism, Disease Models, Animal, Female, Male, Mice, Nuclear Pore metabolism, Nuclear Pore pathology, Progranulins genetics, RNA-Seq, Single-Cell Analysis, TDP-43 Proteinopathies drug therapy, TDP-43 Proteinopathies genetics, Thalamus metabolism, Thalamus pathology, Transcriptome, Microglia metabolism, Microglia pathology, Neurons metabolism, Neurons pathology, Progranulins deficiency, TDP-43 Proteinopathies metabolism, TDP-43 Proteinopathies pathology
- Abstract
Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin
1,2 . However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn-/- microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn-/- microglia are sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deletion of the genes encoding C1qa and C3 mitigates microglial toxicity and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration.- Published
- 2020
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17. Cell-type-specific 3D epigenomes in the developing human cortex.
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Song M, Pebworth MP, Yang X, Abnousi A, Fan C, Wen J, Rosen JD, Choudhary MNK, Cui X, Jones IR, Bergenholtz S, Eze UC, Juric I, Li B, Maliskova L, Lee J, Liu W, Pollen AA, Li Y, Wang T, Hu M, Kriegstein AR, and Shen Y
- Subjects
- CRISPR-Cas Systems, Cell Lineage genetics, Cells, Cultured, Chromatin genetics, Chromatin metabolism, DNA Transposable Elements, Histones chemistry, Histones metabolism, Humans, Imaging, Three-Dimensional, Methylation, Multifactorial Inheritance genetics, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Regulatory Elements, Transcriptional, Reproducibility of Results, Transcription, Genetic, Cells classification, Cells metabolism, Cerebral Cortex cytology, Cerebral Cortex embryology, Epigenome, Epigenomics, Organogenesis genetics
- Abstract
Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone
1,2 . Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.- Published
- 2020
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18. Cell stress in cortical organoids impairs molecular subtype specification.
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Bhaduri A, Andrews MG, Mancia Leon W, Jung D, Shin D, Allen D, Jung D, Schmunk G, Haeussler M, Salma J, Pollen AA, Nowakowski TJ, and Kriegstein AR
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- Humans, Neurons, Organoids, Single-Cell Analysis, Tissue Culture Techniques, Cerebral Cortex cytology, Cerebral Cortex physiology, Neurogenesis, Stress, Physiological
- Abstract
Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex
1,2 . However, the fidelity of organoid models remains unclear3-5 . Here we analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development.- Published
- 2020
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19. Neuronal vulnerability and multilineage diversity in multiple sclerosis.
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Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D, Vistnes S, Stockley JH, Young A, Steindel M, Tung B, Goyal N, Bhaduri A, Mayer S, Engler JB, Bayraktar OA, Franklin RJM, Haeussler M, Reynolds R, Schafer DP, Friese MA, Shiow LR, Kriegstein AR, and Rowitch DH
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- Adult, Animals, Astrocytes metabolism, Astrocytes pathology, Autopsy, Cryopreservation, Female, Homeodomain Proteins metabolism, Humans, Macrophages metabolism, Macrophages pathology, Male, Mice, Microglia metabolism, Microglia pathology, Middle Aged, Multiple Sclerosis genetics, Myelin Sheath metabolism, Neurons metabolism, Oligodendroglia metabolism, Oligodendroglia pathology, Phagocytosis, RNA, Small Nuclear analysis, RNA, Small Nuclear genetics, RNA-Seq, Transcriptome genetics, Cell Lineage, Multiple Sclerosis pathology, Neurons pathology
- Abstract
Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.
- Published
- 2019
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20. Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development.
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Nowakowski TJ, Rani N, Golkaram M, Zhou HR, Alvarado B, Huch K, West JA, Leyrat A, Pollen AA, Kriegstein AR, Petzold LR, and Kosik KS
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- Brain metabolism, Cell Proliferation, High-Throughput Nucleotide Sequencing, Humans, Brain growth & development, Gene Regulatory Networks, MicroRNAs metabolism, Transcriptome
- Abstract
MicroRNAs (miRNAs) regulate many cellular events during brain development by interacting with hundreds of mRNA transcripts. However, miRNAs operate nonuniformly upon the transcriptional profile with an as yet unknown logic. Shortcomings in defining miRNA-mRNA networks include limited knowledge of in vivo miRNA targets and their abundance in single cells. By combining multiple complementary approaches, high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation with an antibody to AGO2 (AGO2-HITS-CLIP), single-cell profiling and computational analyses using bipartite and coexpression networks, we show that miRNA-mRNA interactions operate as functional modules that often correspond to cell-type identities and undergo dynamic transitions during brain development. These networks are highly dynamic during development and over the course of evolution. One such interaction is between radial-glia-enriched ORC4 and miR-2115, a great-ape-specific miRNA, which appears to control radial glia proliferation rates during human brain development.
- Published
- 2018
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21. Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences.
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Hansen DV, Lui JH, Flandin P, Yoshikawa K, Rubenstein JL, Alvarez-Buylla A, and Kriegstein AR
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- Animals, Cell Differentiation, Cell Movement, Fetus, Humans, LIM-Homeodomain Proteins metabolism, Mice, Neocortex anatomy & histology, Nerve Tissue Proteins metabolism, Organ Culture Techniques, RNA, Messenger metabolism, Transcription Factors metabolism, Cerebral Ventricles cytology, GABAergic Neurons physiology, Gene Expression Regulation, Developmental physiology, Interneurons physiology, Multipotent Stem Cells physiology, Neocortex embryology
- Abstract
GABAergic cortical interneurons underlie the complexity of neural circuits and are particularly numerous and diverse in humans. In rodents, cortical interneurons originate in the subpallial ganglionic eminences, but their developmental origins in humans are controversial. We characterized the developing human ganglionic eminences and found that the subventricular zone (SVZ) expanded massively during the early second trimester, becoming densely populated with neural stem cells and intermediate progenitor cells. In contrast with the cortex, most stem cells in the ganglionic eminence SVZ did not maintain radial fibers or orientation. The medial ganglionic eminence exhibited unique patterns of progenitor cell organization and clustering, and markers revealed that the caudal ganglionic eminence generated a greater proportion of cortical interneurons in humans than in rodents. On the basis of labeling of newborn neurons in slice culture and mapping of proliferating interneuron progenitors, we conclude that the vast majority of human cortical interneurons are produced in the ganglionic eminences, including an enormous contribution from non-epithelial SVZ stem cells.
- Published
- 2013
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22. A new subtype of progenitor cell in the mouse embryonic neocortex.
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Wang X, Tsai JW, LaMonica B, and Kriegstein AR
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- Age Factors, Animals, Cell Differentiation, Cell Division, Cell Movement physiology, Centrosome physiology, Embryo, Mammalian, Gene Expression Regulation, Developmental, Green Fluorescent Proteins genetics, Luminescent Proteins genetics, Mice, Mice, Transgenic, Microscopy, Confocal methods, Nerve Tissue Proteins genetics, Neurons physiology, Organ Culture Techniques, Time Factors, Neocortex cytology, Neocortex embryology, Neuroglia physiology, Stem Cells cytology
- Abstract
A hallmark of mammalian brain evolution is cortical expansion, which reflects an increase in the number of cortical neurons established by the progenitor cell subtypes present and the number of their neurogenic divisions. Recent studies have revealed a new class of radial glia-like (oRG) progenitor cells in the human brain, which reside in the outer subventricular zone. Expansion of the subventricular zone and appearance of oRG cells may have been essential evolutionary steps leading from lissencephalic to gyrencephalic neocortex. Here we show that oRG-like progenitor cells are present in the mouse embryonic neocortex. They arise from asymmetric divisions of radial glia and undergo self-renewing asymmetric divisions to generate neurons. Moreover, mouse oRG cells undergo mitotic somal translocation whereby centrosome movement into the basal process during interphase precedes nuclear translocation. Our finding of oRG cells in the developing rodent brain fills a gap in our understanding of neocortical expansion.
- Published
- 2011
- Full Text
- View/download PDF
23. Kinesin 3 and cytoplasmic dynein mediate interkinetic nuclear migration in neural stem cells.
- Author
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Tsai JW, Lian WN, Kemal S, Kriegstein AR, and Vallee RB
- Subjects
- Animals, Cell Cycle physiology, Embryonic Stem Cells cytology, Kinesis physiology, Microtubules physiology, Neural Stem Cells cytology, PC12 Cells, Rats, Cell Movement physiology, Cell Nucleus physiology, Cytoplasmic Dyneins physiology, Embryonic Stem Cells physiology, Kinesins physiology, Neural Stem Cells physiology
- Abstract
Radial glial progenitor cells exhibit bidirectional cell cycle-dependent nuclear oscillations. The purpose and underlying mechanism of this unusual 'interkinetic nuclear migration' are poorly understood. We investigated the basis for this behavior by live imaging of nuclei, centrosomes and microtubules in embryonic rat brain slices, coupled with the use of RNA interference (RNAi) and the myosin inhibitor blebbistatin. We found that nuclei migrated independent of centrosomes and unidirectionally away from or toward the ventricular surface along microtubules, which were uniformly oriented from the ventricular surface to the pial surface of the brain. RNAi directed against cytoplasmic dynein specifically inhibited nuclear movement toward the apical surface. An RNAi screen of kinesin genes identified Kif1a, a member of the kinesin-3 family, as the motor for basally directed nuclear movement. These observations provide direct evidence that kinesins are involved in nuclear migration and neurogenesis and suggest that a cell cycle-dependent switch between distinct microtubule motors drives interkinetic nuclear migration.
- Published
- 2010
- Full Text
- View/download PDF
24. Regenerative medicine: Cell reprogramming gets direct.
- Author
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Nicholas CR and Kriegstein AR
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Fibroblasts metabolism, Humans, Mice, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Oligodendrocyte Transcription Factor 2, POU Domain Factors genetics, POU Domain Factors metabolism, Regenerative Medicine, Transcription Factors genetics, Transcription Factors metabolism, Cell Lineage, Cell Transdifferentiation, Fibroblasts cytology, Neurons cytology, Neurons metabolism
- Published
- 2010
- Full Text
- View/download PDF
25. GABA puts the brake on stem cells.
- Author
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Kriegstein AR
- Subjects
- Animals, Cell Proliferation, Models, Biological, Neurons drug effects, Stem Cells drug effects, gamma-Aminobutyric Acid pharmacology, Neurons physiology, Stem Cells physiology, gamma-Aminobutyric Acid physiology
- Published
- 2005
- Full Text
- View/download PDF
26. Controlling neuron number: does Numb do the math?
- Author
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Castañeda-Castellanos DR and Kriegstein AR
- Subjects
- Animals, Cell Count, Drosophila Proteins, Humans, Brain embryology, Juvenile Hormones physiology, Neurons physiology
- Published
- 2004
- Full Text
- View/download PDF
27. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases.
- Author
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Noctor SC, Martínez-Cerdeño V, Ivic L, and Kriegstein AR
- Subjects
- Animals, Cell Differentiation, Embryo, Mammalian, Immunohistochemistry, Microscopy, Confocal, Neurons physiology, Organ Culture Techniques, Patch-Clamp Techniques, Rats, Stem Cells physiology, Cell Movement physiology, Cerebral Cortex embryology, Neurons cytology, Stem Cells cytology
- Abstract
Precise patterns of cell division and migration are crucial to transform the neuroepithelium of the embryonic forebrain into the adult cerebral cortex. Using time-lapse imaging of clonal cells in rat cortex over several generations, we show here that neurons are generated in two proliferative zones by distinct patterns of division. Neurons arise directly from radial glial cells in the ventricular zone (VZ) and indirectly from intermediate progenitor cells in the subventricular zone (SVZ). Furthermore, newborn neurons do not migrate directly to the cortex; instead, most exhibit four distinct phases of migration, including a phase of retrograde movement toward the ventricle before migration to the cortical plate. These findings provide a comprehensive and new view of the dynamics of cortical neurogenesis and migration.
- Published
- 2004
- Full Text
- View/download PDF
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