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QKI-7 regulates expression of interferon-related genes in human astrocyte glioma cells
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Evolution and Developmental Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Evolution and Developmental Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Evolution and Developmental Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Evolution and Developmental Biology.
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2010 (English)In: PloS one, ISSN 1932-6203, Vol. 5, no 9, e13079- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The human QKI gene, called quaking homolog, KH domain RNA binding (mouse), is a candidate gene for schizophrenia encoding an RNA-binding protein. This gene was shown to be essential for myelination in oligodendrocytes. QKI is also highly expressed in astrocytes, but its function in these cells is not known. METHODS/PRINCIPAL FINDINGS: We studied the effect of small interference RNA (siRNA)-mediated QKI depletion on global gene expression in human astrocyte glioma cells. Microarray measurements were confirmed with real-time quantitative polymerase chain reaction (qPCR). The presence of QKI binding sites (QRE) was assessed by a bioinformatic approach. Viability and cell morphology were also studied. The most significant alteration after QKI silencing was the decreased expression of genes involved in interferon (IFN) induction (P = 6.3E-10), including IFIT1, IFIT2, MX1, MX2, G1P2, G1P3, GBP1 and IFIH1. All eight genes were down-regulated after silencing of the splice variant QKI-7, but were not affected by QKI-5 silencing. Interestingly, four of them were up-regulated after treatment with the antipsychotic agent haloperidol that also resulted in increased QKI-7 mRNA levels. CONCLUSIONS/SIGNIFICANCE: The coordinated expression of QKI-7 splice variant and IFN-related genes supports the idea that this particular splice variant has specific functions in astrocytes. Furthermore, a role of QKI-7 as a regulator of an inflammatory gene pathway in astrocytes is suggested. This hypothesis is well in line with growing experimental evidence on the role of inflammatory components in schizophrenia.

Place, publisher, year, edition, pages
2010. Vol. 5, no 9, e13079- p.
National Category
Biological Sciences Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-132707DOI: 10.1371/journal.pone.0013079ISI: 000282269400026PubMedID: 20927331OAI: oai:DiVA.org:uu-132707DiVA: diva2:358899
Available from: 2010-10-25 Created: 2010-10-25 Last updated: 2014-05-20Bibliographically approved
In thesis
1. Functional studies of the Quaking gene: Focus on astroglia and neurodevelopment
Open this publication in new window or tab >>Functional studies of the Quaking gene: Focus on astroglia and neurodevelopment
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The RNA-binding protein Quaking (QKI) plays a fundamental role in post-transcriptional gene regulation during mammalian nervous system development. QKI is well known for advancing oligodendroglia differentiation and myelination, however, its functions in astrocytes and embryonic central nervous system (CNS) development remain poorly understood. Uncovering the complete spectrum of QKI molecular and functional repertoire is of additional importance in light of growing evidence linking QKI dysfunction with human disease, including schizophrenia and glioma. This thesis summarizes my contribution to fill this gap of knowledge. 

       In a first attempt to identify the QKI-mediated molecular pathways in astroglia, we studied the effects of QKI depletion on global gene expression in the human astrocytoma cell line. This work revealed a previously unknown role of QKI in regulating immune-related pathways. In particular, we identified several putative mRNA targets of QKI involved in interferon signaling, with possible implications in innate cellular antiviral defense, as well as tumor suppression. We next extended these investigations to human primary astrocytes, in order to more accurately model normal brain astrocytes. One of the most interesting outcomes of this analysis was that QKI regulates expression of transcripts encoding the Glial Fibrillary Acidic Protein, an intermediate filament protein that mediates diverse biological functions of astrocytes and is implicated in numerous CNS pathologies. We also characterized QKI splice variant composition and subcellular expression of encoded protein isoforms in human astrocytes. Finally, we explored the potential use of zebrafish as a model system to study neurodevelopmental functions of QKI in vivo. Two zebrafish orthologs, qkib and qki2, were identified and found to be widely expressed in the CNS neural progenitor cell domains. Furthermore, we showed that a knockdown of qkib perturbs the development of both neuronal and glial populations, and propose neural progenitor dysfunction as the primary cause of the observed phenotypes.

       To conclude, the work presented in this thesis provides the first insight into understanding the functional significance of the human QKI in astroglia, and introduces zebrafish as a novel tool with which to further investigate the importance of this gene in neural development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1152
Keyword
QKI, RNA-binding protein, astrocyte, interferon, GFAP, neurodevelopment, zebrafish, neural progenitor cell
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-223332 (URN)978-91-554-8960-1 (ISBN)
Public defence
2014-06-12, Lindahlsalen, Norbevagen 18, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2014-05-20 Created: 2014-04-17 Last updated: 2014-06-30Bibliographically approved

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