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RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in human astrocytes
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
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2013 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, no 7, 1373-1382 p.Article in journal (Refereed) Published
Abstract [en]

Linkage, association and expression studies previously pointed to the human QKI, KH domain containing, RNA-binding (QKI) as a candidate gene for schizophrenia. Functional studies of the mouse orthologue Qk focused mainly on its role in oligodendrocyte development and myelination, while its function in astroglia remained unexplored. Here, we show that QKI is highly expressed in human primary astrocytes and that its splice forms encode proteins targeting different subcellular localizations. Uncovering the role of QKI in astrocytes is of interest in light of growing evidence implicating astrocyte dysfunction in the pathogenesis of several disorders of the central nervous system. We selectively silenced QKI splice variants in human primary astrocytes and used RNA sequencing to identify differential expression and splice variant composition at the genome-wide level. We found that an mRNA expression of Glial fibrillary acidic protein (GFAP), encoding a major component of astrocyte intermediate filaments, was down-regulated after QKI7 splice variant silencing. Moreover, we identified a potential QKI-binding site within the 3 untranslated region of human GFAP. This sequence was not conserved between mice and humans, raising the possibility that GFAP is a target for QKI in humans but not rodents. Haloperidol treatment of primary astrocytes resulted in coordinated increases in QKI7 and GFAP expression. Taken together, our results provide the first link between QKI and GFAP, two genes with alterations previously observed independently in schizophrenic patients. Our findings for QKI, together with its well-known role in myelination, suggest that QKI is a hub regulator of glia function in humans.

Place, publisher, year, edition, pages
2013. Vol. 22, no 7, 1373-1382 p.
National Category
Natural Sciences Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-198376DOI: 10.1093/hmg/dds553ISI: 000316297000009OAI: oai:DiVA.org:uu-198376DiVA: diva2:616212
Available from: 2013-04-15 Created: 2013-04-15 Last updated: 2017-12-06Bibliographically 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
2. Sequence based analysis of neurodevelopmental disorders
Open this publication in new window or tab >>Sequence based analysis of neurodevelopmental disorders
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis the main focus is the use of methods and applications of next generation sequencing in order to study three of the most common neurodevelopmental disorders: intellectual disability, epilepsy and schizophrenia. A large fraction of the genes in our genome produce several distinct transcript isoforms through the process of splicing and there is an increasing amount of evidence pinpointing mutations affecting splicing as a mechanism of disease.  In Paper I we used exome capture of RNA in combination with sequencing in order to enrich for coding sequences. We show that this approach enables us to detect lowly expressed transcript and splice events that would have been missed in regular RNA sequencing using the same coverage.  In Paper II we selectively depleted the different transcripts of Quaking (QKI), a gene previously associated to schizophrenia. Using RNA sequencing we show that the effects of depletion differ between transcripts and that the QKI gene is a potential regulator of the Glial Fibrillary Acidic Protein (GFAP), a gene implicated in several diseases in the central nervous system.

De-novo mutations are frequently reported to be causative in neurodevelopmental disorders with a strong genetic component, such as epilepsy and intellectual disability. In Paper III we used exome sequencing in family trios where the child was diagnosed with both intellectual disability and epilepsy, focusing on finding de-novo mutations. We identified several previously unknown disease causing mutations in genes previously known to cause disease and used previously published interaction and mutation data to prioritize novel candidate genes. The most interesting result from this study are the implication of the HECW2 gene as a candidate gene in intellectual disability and epilepsy. In Paper IV we used RNA sequencing of post mortem brain tissue in a large cohort of schizophrenics and controls.  In this study we could show that the immune system and more specifically the complement system was dysregulated in a large fraction of patients. Further, using co-expression network we also found some evidence suggesting genes involved in axon development and maintenance.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1231
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-287407 (URN)978-91-554-9597-8 (ISBN)
Public defence
2016-06-14, C2:305, BMC, Husargatan 3, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2016-05-20 Created: 2016-04-24 Last updated: 2016-06-15

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Radomska, Katarzyna J.Halvardson, JonatanReinius, BjörnCarlström, Eva LindholmEmilsson, LinaFeuk, LarsJazin, Elena

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