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  1. Article ; Online: Transcriptome analysis reveals the contribution of oligodendrocyte and radial glia-derived cues for maintenance of microglia identity.

    Timmerman, Raissa / Zuiderwijk-Sick, Ella A / Oosterhof, Nynke / 't Jong, Anke E J / Veth, Jennifer / Burm, Saskia M / van Ham, Tjakko J / Bajramovic, Jeffrey J

    Glia

    2021  Volume 70, Issue 4, Page(s) 728–747

    Abstract: Microglia are increasingly being recognized as druggable targets in neurodegenerative disorders, and good in vitro models are crucial to address cell biological questions. Major challenges are to recapitulate the complex microglial morphology and their ... ...

    Abstract Microglia are increasingly being recognized as druggable targets in neurodegenerative disorders, and good in vitro models are crucial to address cell biological questions. Major challenges are to recapitulate the complex microglial morphology and their in vivo transcriptome. We have therefore exposed primary microglia from adult rhesus macaques to a variety of different culture conditions including exposure to soluble factors as M-CSF, IL-34, and TGF-β as well as serum replacement approaches, and compared their morphologies and transcriptomes to those of mature, homeostatic in vivo microglia. This enabled us to develop a new, partially serum-free, monoculture protocol, that yields high numbers of ramified cells. We also demonstrate that exposure of adult microglia to M-CSF or IL-34 induces similar transcriptomes, and that exposure to TGF-β has much less pronounced effects than it does on rodent microglia. However, regardless of culture conditions, the transcriptomes of in vitro and in vivo microglia remained substantially different. Analysis of differentially expressed genes inspired us to perform 3D-spherical coculture experiments of microglia with oligodendrocytes and radial glia. In such spheres, microglia signature genes were strongly induced, even in the absence of neurons and astrocytes. These data reveal a novel role for oligodendrocyte and radial glia-derived cues in the maintenance of microglial identity, providing new anchor points to study microglia in health and disease.
    MeSH term(s) Animals ; Cues ; Ependymoglial Cells ; Gene Expression Profiling ; Macaca mulatta ; Microglia ; Oligodendroglia ; Transcriptome
    Language English
    Publishing date 2021-12-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 639414-0
    ISSN 1098-1136 ; 0894-1491
    ISSN (online) 1098-1136
    ISSN 0894-1491
    DOI 10.1002/glia.24136
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2345: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: In trans paired nicking triggers seamless genome editing without double-stranded DNA cutting.

    Chen, Xiaoyu / Janssen, Josephine M / Liu, Jin / Maggio, Ignazio / 't Jong, Anke E J / Mikkers, Harald M M / Gonçalves, Manuel A F V

    Nature communications

    2017  Volume 8, Issue 1, Page(s) 657

    Abstract: Precise genome editing involves homologous recombination between donor DNA and chromosomal sequences subjected to double-stranded DNA breaks made by programmable nucleases. Ideally, genome editing should be efficient, specific, and accurate. However, ... ...

    Abstract Precise genome editing involves homologous recombination between donor DNA and chromosomal sequences subjected to double-stranded DNA breaks made by programmable nucleases. Ideally, genome editing should be efficient, specific, and accurate. However, besides constituting potential translocation-initiating lesions, double-stranded DNA breaks (targeted or otherwise) are mostly repaired through unpredictable and mutagenic non-homologous recombination processes. Here, we report that the coordinated formation of paired single-stranded DNA breaks, or nicks, at donor plasmids and chromosomal target sites by RNA-guided nucleases based on CRISPR-Cas9 components, triggers seamless homology-directed gene targeting of large genetic payloads in human cells, including pluripotent stem cells. Importantly, in addition to significantly reducing the mutagenicity of the genome modification procedure, this in trans paired nicking strategy achieves multiplexed, single-step, gene targeting, and yields higher frequencies of accurately edited cells when compared to the standard double-stranded DNA break-dependent approach.CRISPR-Cas9-based gene editing involves double-strand breaks at target sequences, which are often repaired by mutagenic non-homologous end-joining. Here the authors use Cas9 nickases to generate coordinated single-strand breaks in donor and target DNA for precise homology-directed gene editing.
    MeSH term(s) CRISPR-Cas Systems ; Cell Line ; DNA/genetics ; DNA/metabolism ; DNA Breaks, Double-Stranded ; DNA Breaks, Single-Stranded ; DNA End-Joining Repair ; Gene Editing ; Genome, Human ; Humans ; RNA, Guide, CRISPR-Cas Systems/genetics ; RNA, Guide, CRISPR-Cas Systems/metabolism
    Chemical Substances RNA, Guide, CRISPR-Cas Systems ; DNA (9007-49-2)
    Language English
    Publishing date 2017-09-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-017-00687-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Allele-specific repression of Sox2 through the long non-coding RNA Sox2ot.

    Messemaker, Tobias C / van Leeuwen, Selina M / van den Berg, Patrick R / 't Jong, Anke E J / Palstra, Robert-Jan / Hoeben, Rob C / Semrau, Stefan / Mikkers, Harald M M

    Scientific reports

    2018  Volume 8, Issue 1, Page(s) 386

    Abstract: The transcription factor Sox2 controls the fate of pluripotent stem cells and neural stem cells. This gatekeeper function requires well-regulated Sox2 levels. We postulated that Sox2 regulation is partially controlled by the Sox2 overlapping long non- ... ...

    Abstract The transcription factor Sox2 controls the fate of pluripotent stem cells and neural stem cells. This gatekeeper function requires well-regulated Sox2 levels. We postulated that Sox2 regulation is partially controlled by the Sox2 overlapping long non-coding RNA (lncRNA) gene Sox2ot. Here we show that the RNA levels of Sox2ot and Sox2 are inversely correlated during neural differentiation of mouse embryonic stem cells (ESCs). Through allele-specific enhanced transcription of Sox2ot in mouse Sox2eGFP knockin ESCs we demonstrate that increased Sox2ot transcriptional activity reduces Sox2 RNA levels in an allele-specific manner. Enhanced Sox2ot transcription, yielding lower Sox2 RNA levels, correlates with a decreased chromatin interaction of the upstream regulatory sequence of Sox2 and the ESC-specific Sox2 super enhancer. Our study indicates that, in addition to previously reported in trans mechanisms, Sox2ot can regulate Sox2 by an allele-specific mechanism, in particular during development.
    MeSH term(s) Alleles ; Animals ; Cell Differentiation ; Gene Expression Regulation, Developmental ; Gene Knock-In Techniques ; Mice ; Mouse Embryonic Stem Cells/cytology ; Neurogenesis ; RNA, Long Noncoding/genetics ; SOXB1 Transcription Factors/genetics ; Transcription, Genetic
    Chemical Substances RNA, Long Noncoding ; SOXB1 Transcription Factors ; Sox2 protein, mouse ; long noncoding RNA Sox2OT, mouse
    Language English
    Publishing date 2018-01-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-017-18649-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Inflammasome-induced IL-1β secretion in microglia is characterized by delayed kinetics and is only partially dependent on inflammatory caspases.

    Burm, Saskia M / Zuiderwijk-Sick, Ella A / 't Jong, Anke E J / van der Putten, Céline / Veth, Jennifer / Kondova, Ivanela / Bajramovic, Jeffrey J

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2015  Volume 35, Issue 2, Page(s) 678–687

    Abstract: Inflammasomes are multiprotein complexes that link pathogen recognition and cellular stress to the processing of the proinflammatory cytokine interleukin-1β (IL-1β). Whereas inflammasome-mediated activation is heavily studied in hematopoietic macrophages ...

    Abstract Inflammasomes are multiprotein complexes that link pathogen recognition and cellular stress to the processing of the proinflammatory cytokine interleukin-1β (IL-1β). Whereas inflammasome-mediated activation is heavily studied in hematopoietic macrophages and dendritic cells, much less is known about microglia, resident tissue macrophages of the brain that originate from a distinct progenitor. To directly compare inflammasome-mediated activation in different types of macrophages, we isolated primary microglia and hematopoietic macrophages from adult, healthy rhesus macaques. We analyzed the expression profile of NOD (nucleotide-binding oligomerization domain)-like receptors, adaptor proteins, and caspases and characterized inflammasome activation and regulation in detail. We here demonstrate that primary microglia can respond to the same innate stimuli as hematopoietic macrophages. However, microglial responses are more persistent due to lack of negative regulation on pro-IL-1β expression. In addition, we show that while caspase 1, 4, and 5 activation is pivotal for inflammasome-induced IL-1β secretion by hematopoietic macrophages, microglial secretion of IL-1β is only partially dependent on these inflammatory caspases. These results identify key cell type-specific differences that may aid the development of strategies to modulate innate immune responses in the brain.
    MeSH term(s) Animals ; Caspases/genetics ; Caspases/metabolism ; Cells, Cultured ; Female ; Inflammasomes/metabolism ; Interleukin-1beta/genetics ; Interleukin-1beta/metabolism ; Kinetics ; Macaca mulatta ; Macrophages/metabolism ; Male ; Microglia/metabolism ; Nod1 Signaling Adaptor Protein/genetics ; Nod1 Signaling Adaptor Protein/metabolism ; Nod2 Signaling Adaptor Protein/genetics ; Nod2 Signaling Adaptor Protein/metabolism ; Reaction Time
    Chemical Substances Inflammasomes ; Interleukin-1beta ; Nod1 Signaling Adaptor Protein ; Nod2 Signaling Adaptor Protein ; Caspases (EC 3.4.22.-)
    Language English
    Publishing date 2015-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.2510-14.2015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1668: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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