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QKI6B is upregulated in schizophrenic brains and predicts GFAP expression
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.ORCID iD: 0000-0003-3459-0451
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology. Institut de Biologie de l'École Normale Supérieure, Department of Biology .
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
University of Gothenburg, The Sahlgrenska Academy, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology.
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(English)In: Schizophrenia Research, ISSN 0920-9964, E-ISSN 1573-2509Article in journal (Other academic) Submitted
Abstract [en]

Schizophrenia is a highly heritable disorder with a heterogeneous symptomatology. Research increasingly indicates the importance of the crucial and often overlooked glial perturbations within schizophrenic brains. Within this study, we examined an isoform of quaking (gene encoding an RNA-binding protein that is exclusively expressed in glial cells), known as QKI6B, and an astrocyte marker glial fibrillary acidic protein (GFAP), postulated to be under the regulation of QKI. The expression levels of these genes were quantified across post-mortem samples from the prefrontal cortex of 55 schizophrenic brains, and 55 healthy control brains, using real-time PCR. We report, through an analysis of covariance (ANCOVA) model, an upregulation of both QKI6B, and GFAP in the prefrontal cortex of schizophrenic brains. Previous research has suggested that the QKI protein directly regulates the expression of several genes through interaction with a motif in the target’s sequence, termed the Quaking Response Element (QRE). We therefore examined if QKI6B expression can predict the outcome of GFAP, and several oligodendrocyte-related genes, using a multiple linear regression approach. We found that QKI6B significantly predicts, and possibly regulates the expression of GFAP, but does not predict oligodendrocyte-related gene outcome, as previously seen with other QKI isoforms. 

National Category
URN: urn:nbn:se:uu:diva-284637OAI: oai:DiVA.org:uu-284637DiVA: diva2:920805
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2016-06-01
In thesis
1. Translational research of the quaking gene: Focusing on the conjunction between development and disease
Open this publication in new window or tab >>Translational research of the quaking gene: Focusing on the conjunction between development and disease
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Quaking (QKI) is an RNA binding protein involved in the post-transcriptional regulation of gene expression. Originally identified as the cause of hypomyelination in a mouse mutant, it has since been consistently implicated in a wide range of neurological diseases. As a gene exclusively expressed in glial cells of the central nervous system, such associations emphasise the importance of an indirect, or non-neuronal link to aberrant neural function. A role in early neural development has also been suggested from the viable and embryonic lethal mouse mutants, yet detailed and in vivo study has been precluded thus far by the murine uterine gestation, and mutant lethality prior to oligodendrogenesis. This thesis examines the role of QKI in human neurological disease, and explores the use of the zebrafish as a model organism to allow the unimpeded study of neural development.

We first examined the expression of QKI in human post-mortem brain samples, in separate studies of Alzheimer’s disease (AD) and schizophrenia. In AD we found that QKI and the splice variants QKI5, QKI6, and QKI7 were all significantly upregulated, and were additionally implicated in the regulation of genes related to AD pathogenesis. Within schizophrenic samples, we explored the expression of QKI6B, a newly identified splice variant of QKI, alongside GFAP. We found that both were significantly upregulated, and a previously implicated regulation of GFAP by QKI was supported. In order to advance investigations of the potential of QKI to disturb neural development, we established the suitability of zebrafish for studying qki. This was achieved through phylogenetic and syntenic analysis, coupled with examination of the qki genes expression patterns. We found that qkib and qki2 are orthologues of human QKI, and both have distinct, yet overlapping expression patterns in neural progenitors, and are not found in differentiated neurons. Following from this, we explored the effects of knockdown to qkib and qki2, finding that qkib exclusively led to aberrant motor neuron development, cerebellar abnormalities, and alterations to the progenitor domain. This clearly demonstrated the crucial role of qki in early neural development, and confirms a previously speculated, yet occluded, function prior to oligodendrogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1381
QKI, glia, oligodendrocyte, Alzheimer's, schizophrenia, zebrafish, statistics, morpholino
National Category
Genetics Developmental Biology Neurosciences
Research subject
Biology with specialization in Evolutionary Organismal Biology
urn:nbn:se:uu:diva-287408 (URN)978-91-554-9595-4 (ISBN)
Public defence
2016-06-14, Zootisalen, EBC, Norbyvägen 18A, Uppsala, 13:00 (English)
Available from: 2016-05-17 Created: 2016-04-24 Last updated: 2016-06-01

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Farnsworth, BrynEmilsson, Lina
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