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Morpholino knockdown of qkib leads to disturbed neural development in the larval zebrafish.
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.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
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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
Identifiers
URN: urn:nbn:se:uu:diva-287372OAI: oai:DiVA.org:uu-287372DiVA: diva2:922656
Available from: 2016-04-24 Created: 2016-04-24 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1381
Keyword
QKI, glia, oligodendrocyte, Alzheimer's, schizophrenia, zebrafish, statistics, morpholino
National Category
Genetics Developmental Biology Neurosciences
Research subject
Biology with specialization in Evolutionary Organismal Biology
Identifiers
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)
Opponent
Supervisors
Available from: 2016-05-17 Created: 2016-04-24 Last updated: 2016-06-01

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Farnsworth, Bryn
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