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Translational research of the quaking gene: Focusing on the conjunction between development and disease
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.ORCID iD: 0000-0003-3459-0451
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
Keyword [en]
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: urn:nbn:se:uu:diva-287408ISBN: 978-91-554-9595-4OAI: diva2:922699
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
List of papers
1. Gene Expression of Quaking in Sporadic Alzheimer’s Disease Patients is Both Upregulated and Related to Expression Levels of Genes Involved in Amyloid Plaque and Neurofibrillary Tangle Formation
Open this publication in new window or tab >>Gene Expression of Quaking in Sporadic Alzheimer’s Disease Patients is Both Upregulated and Related to Expression Levels of Genes Involved in Amyloid Plaque and Neurofibrillary Tangle Formation
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2016 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 53, no 1, 209-219 p.Article in journal (Refereed) Published
Abstract [en]

Quaking (QKI) is a gene exclusively expressed within glial cells. QKI has previously been implicated in various neurological disorders and diseases, including Alzheimer’s disease (AD), a condition for which increasing evidence suggests a central role of glia cells. The objective of the present study was to investigate the expression levels of QKI and three QKI isoforms (QKI5, QKI6, and QKI7) in AD. Genes that have previously been related to the ontogeny and progression of AD, specifically APP, PSEN1, PSEN2, and MAPT, were also investigated. A real-time PCR assay of 123 samples from human postmortem sporadic AD patients and control brains was performed. The expression values were analyzed with an analysis of covariance model and subsequent multiple regressions to explore the possibility of related expression values between QKI, QKI isoforms, and AD-related genes. Further, the sequences of AD-related genes were analyzed for the presence of QKI binding domains. QKI and all measured QKI isoforms were found to be significantly upregulated in AD samples, relative to control samples. However, APP, PSEN1, PSEN2, and MAPT were not found to be significantly different. QKI and QKI isoforms were found to be predictive for the variance of APP, PSEN1, PSEN2, and MAPT, and putative QKI binding sites suggests an interaction with QKI. Overall, these results implicate a possible role of QKI in AD, although the exact mechanism by which this occurs remains to be uncovered.

Place, publisher, year, edition, pages
IOS Press, 2016
Amyloid-beta, APP, gene expression, glia, MAPT, neurodegenerative diseases, real-time polymerase chain reaction, PSEN1, PSEN2
National Category
Genetics Neurosciences
urn:nbn:se:uu:diva-286589 (URN)10.3233/JAD-160160 (DOI)
Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyTorsten Söderbergs stiftelseSwedish Society of MedicineMagnus Bergvall FoundationLars Hierta Memorial FoundationEU, FP7, Seventh Framework Programme, 608743
Available from: 2016-04-21 Created: 2016-04-21 Last updated: 2016-08-24Bibliographically approved
2. QKI6B is upregulated in schizophrenic brains and predicts GFAP expression
Open this publication in new window or tab >>QKI6B is upregulated in schizophrenic brains and predicts GFAP expression
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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:nbn:se:uu:diva-284637 (URN)
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2016-06-01
3. Characterization and Expression of the Zebrafish qki Paralogs
Open this publication in new window or tab >>Characterization and Expression of the Zebrafish qki Paralogs
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, e0146155Article in journal (Refereed) Published
Abstract [en]

Quaking (QKI) is an RNA-binding protein involved in post-transcriptional mRNA processing. This gene is found to be associated with several human neurological disorders. Early expression of QKI proteins in the developing mouse neuroepithelium, together with neural tube defects in Qk mouse mutants, suggest the functional requirement of Qk for the establishment of the nervous system. As a knockout of Qk is embryonic lethal in mice, other model systems like the zebrafish could serve as a tool to study the developmental functions of qki. In the present study we sought to characterize the evolutionary relationship and spatiotemporal expression of qkia, qki2, and qkib; zebrafish homologs of human QKI. We found that qkia is an ancestral paralog of the single tetrapod Qk gene that was likely lost during the fin-to-limb transition. Conversely, qkib and qki2 are orthologs, emerging at the root of the vertebrate and teleost lineage, respectively. Both qki2 and qkib, but not qkia, were expressed in the progenitor domains of the central nervous system, similar to expression of the single gene in mice. Despite having partially overlapping expression domains, each gene has a unique expression pattern, suggesting that these genes have undergone subfunctionalization following duplication. Therefore, we suggest the zebrafish could be used to study the separate functions of qki genes during embryonic development.

National Category
Developmental Biology
urn:nbn:se:uu:diva-275551 (URN)10.1371/journal.pone.0146155 (DOI)000367681500058 ()26727370 (PubMedID)
Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology, 1152Carl Tryggers foundation , CTS12:116Carl Tryggers foundation , CTS13:116Carl Tryggers foundation , CTS14:128The Swedish Brain FoundationMagnus Bergvall FoundationLars Hierta Memorial Foundation
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2016-06-01Bibliographically approved
4. Morpholino knockdown of qkib leads to disturbed neural development in the larval zebrafish.
Open this publication in new window or tab >>Morpholino knockdown of qkib leads to disturbed neural development in the larval zebrafish.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Quaking (QKI) is a member of the Signal Transduction and Activation of RNA (STAR) protein family and has been found to regulate the splicing, quantity, and translation of mRNA. Several studies have also found an association of QKI with a variety of human neurological disorders, such as schizophrenia, ataxia, and Alzheimer’s disease, amongst others. Mouse mutants show clear developmental defects in myelin formation. Critical periods for the investigation of myelin aberration have been precluded by the embryonic lethality of Qk null mice mutants. We have previously shown that the zebrafish is a suitable tool in which to interrogate qki function. Within this study we employ a gene-knockdown approach with the use of morpholinos and the Tg(olig2:DsRed2), and Tg(-4.9sox10:eGFP) transgenic zebrafish lines, and confocal imaging. We find a reduction in the number of oligodendrocytes, critical for the formation of myelin. We also find aberrations in the development and arborization of motor neurons across the spinal cord, and a complete absence of eurydendroid cells within the cerebellum. These findings have parallels to both neuroanatomical evidence from viable Qk mutant mice, and to aspects of related human neurological disease.

National Category
Genetics Developmental Biology
urn:nbn:se:uu:diva-287372 (URN)
Available from: 2016-04-24 Created: 2016-04-24 Last updated: 2016-06-01

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