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Characterization and Expression of the Zebrafish qki Paralogs
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
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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
Resource type
Text
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.

Place, publisher, year, edition, pages
2016. Vol. 11, no 1, e0146155
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-275551DOI: 10.1371/journal.pone.0146155ISI: 000367681500058PubMedID: 26727370OAI: oai:DiVA.org:uu-275551DiVA: diva2:900623
Funder
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: 2017-11-30Bibliographically approved
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)
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Available from: 2016-05-17 Created: 2016-04-24 Last updated: 2016-06-01

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Farnsworth, BrynJazin, ElenaEmilsson, Lina S.

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