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Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia.

Cell stem cell | 2017

In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep. RNA-seq of cultured SCZ human glial progenitor cells (hGPCs) revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell autonomous. Our data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia and provide a humanized model for its in vivo assessment.

Pubmed ID: 28736215 RIS Download

Mesh terms: Animals | Astrocytes | Behavior | Cell Differentiation | Chimera | Gene Expression Regulation | Humans | Induced Pluripotent Stem Cells | Mice | Myelin Sheath | Neuroglia | Phenotype | Schizophrenia

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edgeR (tool)

RRID:SCR_012802

Bioconductor software package for Empirical analysis of Digital Gene Expression data in R. Used for differential expression analysis of RNA-seq and digital gene expression data with biological replication.

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Subread (tool)

RRID:SCR_009803

A toolkit for processing next-gen sequencing data. These programs were also implemented in Bioconductor R package Rsubread.

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BD Biosciences (tool)

RRID:SCR_013311

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Neurolucida (tool)

RRID:SCR_001775

Neurolucida is advanced scientific software for brain mapping, neuron reconstruction, anatomical mapping, and morphometry. Since its debut more than 20 years ago, Neurolucida has continued to evolve and has become the worldwide gold-standard for neuron reconstruction and 3D mapping. Neurolucida has the flexibility to handle data in many formats: using live images from digital or video cameras; stored image sets from confocal microscopes, electron microscopes, and scanning tomographic sources, or through the microscope oculars using the patented LucividTM. Neurolucida controls a motorized XYZ stage for integrated navigation through tissue sections, allowing for sophisticated analysis from many fields-of-view. Neurolucidas Serial Section Manager integrates unlimited sections into a single data file, maintaining each section in aligned 3D space for full quantitative analysis. Neurolucidas neuron tracing capabilities include 3D measurement and reconstruction of branching processes. Neurolucida also features sophisticated tools for mapping delineate and map anatomical regions for detailed morphometric analyses. Neurolucida uses advanced computer-controlled microscopy techniques to obtain accurate results and speed your work. Plug-in modules are available for confocal and MRI analysis, 3D solid modeling, and virtual slide creation. The user-friendly interface gives you rapid results, allowing you to acquire data and capture the full 3D extent of neurons and brain regions. You can reconstruct neurons or create 3D serial reconstructions directly from slides or acquired images, and Neurolucida offers full microscope control for brightfield, fluorescent, and confocal microscopes. Its added compatibility with 64-bit Microsoft Vista enables reconstructions with even larger images, image stacks, and virtual slides. Adding the Solid Modeling Module allows you to rotate and view your reconstructions in real time. Neurolucida is available in two separate versions Standard and Workstation. The Standard version enables control of microscope hardware, whereas the Workstation version is used for offline analysis away from the microscope. Neurolucida provides quantitative analysis with results presented in graphical or spreadsheet format exportable to Microsoft Excel. Overall, features include: - Tracing Neurons - Anatomical Mapping - Image Processing and Analysis Features - Editing - Morphometric Analysis - Hardware Integration - Cell Analysis - Visualization Features Sponsors: Neurolucida is supported by MBF Bioscience.

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dbGaP at NCBI (tool)

RRID:SCR_002709

Database to archive and distribute the results of studies that have investigated the interaction of genotype and phenotype, including genome-wide association studies, medical sequencing, molecular diagnostic assays, and association between genotype and non-clinical traits. dbGaP provides two types of access for users, open and controlled. Summaries of studies and the contents of measured variables as well as original study document text are generally available to the public, while access to individual-level data including phenotypic data tables and genotypes require varying levels of authorization. The data in dbGaP will be pre-competitive, and will not be protected by intellectual property patents. Investigators who agree to the terms of dbGaP data use may not restrict other investigators' use of primary dbGaP data by filing intellectual property patents on it. However, the use of primary data from dbGaP to develop commercial products and tests to meet public health needs is encouraged. Submitters who are not Federally-funded and affiliated with an NIH IC will need to work with an NIH DAC so that proposed submission can be reviewed for consistency with appropriate policies to protect the privacy of research participants and confidentiality of their data. Submissions to dbGaP will not be accepted without assurance that the submitting institution approves the submission and has verified that the data submission is consistent with all applicable laws and regulations, as well as institutional policies. Submitters must also identify any limits on research uses of the data that are specifically set by individual research participants, e.g., through their informed consent. Open-access data can be browsed online or downloaded from dbGaP without prior permission or authorization.

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Ki-67 antibody (antibody)

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CD44-APC, human antibody (antibody)

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Goat anti-Mouse IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor 488 (antibody)

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Anti-Chondroitin Sulfate Proteoglycan Antibody (antibody)

RRID:AB_94509

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Goat anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor 647 (antibody)

RRID:AB_2535813

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Human Olig2 Affinity Purified Polyclonal Ab antibody (antibody)

RRID:AB_2157554

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Mouse IgM-APC antibody (antibody)

RRID:AB_871720

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Mouse Anti-IgG1 IgG1 Monoclonal Antibody ; Isotype Control, APC Conjugated Clone IS5-21F5 (antibody)

RRID:AB_871704

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Transferrin antibody (antibody)

RRID:AB_307325

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Mouse IgG2a, k antibody (antibody)

RRID:AB_395953

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Anti-A2B5-APC antibody (antibody)

RRID:AB_10827602

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CD140a antibody (antibody)

RRID:AB_396286

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RAT ANTI BrdU antibody (antibody)

RRID:AB_323427

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Goat anti-Mouse IgG1 Cross-Adsorbed Secondary Antibody, Alexa Fluor 568 (antibody)

RRID:AB_2535766

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Mouse Anti-Human CD133/1 (AC133) Monoclonal Antibody, APC Conjugated Clone AC133 (antibody)

RRID:AB_244340

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PDGF Receptor (D13C6) XP Rabbit mAb antibody (antibody)

RRID:AB_10692773

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