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| 2. |
- Farnsworth, Bryn, et al.
(författare)
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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
- 2016
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 53:1, s. 209-219
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Farnsworth, Bryn, et al.
(författare)
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Morpholino knockdown of qkib leads to disturbed neural development in the larval zebrafish.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 4. |
- Farnsworth, Bryn, et al.
(författare)
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QKI6B is upregulated in schizophrenic brains and predicts GFAP expression
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Ingår i: Schizophrenia Research. - 0920-9964 .- 1573-2509.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 5. |
- Farnsworth, B., 1987-, et al.
(författare)
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QKI6B mRNA levels are upregulated in schizophrenia and predict GFAP expression
- 2017
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1669, s. 63-68
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a highly heritable disorder with a heterogeneous symptomatology. Research increasingly indicates the importance of the crucial and often overlooked glial perturbations within schizophrenia. Within this study, we examined an isoform of quaking (a gene encoding an RNA-binding protein that is exclusively expressed in glial cells), known as QKI6B, and a prototypical 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 brain samples from 55 schizophrenic individuals, and 55 healthy controls, 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 brain samples of schizophrenic individuals, as compared to control samples. 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 QICI6B expression can predict the outcome of GFAP, and several oligodendrocyte-related genes, using a multiple linear regression approach. We found that QKI6B significantly predicts the expression of GFAP, but does not predict oligodendrocyte-related gene outcome, as previously seen with other QKI isoforms.
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| 6. |
- Landin, Jenny, et al.
(författare)
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Oxytocin Receptors Regulate Social Preference in Zebrafish.
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- With a strong tendency to socialise, the zebrafish is a useful model to study social behaviour, with implications for better treatments of social impairments, for instance in autism spectrum disorders. Although oxytocin is crucial for social behaviour in mammals, the importance of the fish orthologue - isotocin or zebrafish oxytocin (zOT) - for social behaviour in zebrafish is unclear. The aims of this study were firstly, to elucidate the receptor specificity of zOT and the related vasotocin or zebrafish vasopressin (zVP; the orthologue of mammalian vasopressin) and the nonpeptidergic oxytocin receptor antagonist L-368,899, and secondly to investigate if L-368,899 inhibits social preference in zebrafish. The potencies of ligands were evaluated for zOT/zVP family receptors in HEK293 cells. Adult and larval zebrafish were treated with L-368,899 or vehicle and subsequently assessed for social behaviour and anxiety (adults only). The antagonist L-368,899 specifically inhibited the two zOT receptors, but not the two zVP-1 receptors. The antagonist decreased social preference in adult and larval zebrafish. It did not affect anxiety in adults. These results indicate that endogenous zOT, and possibly zVP, is involved in social behaviour in zebrafish via either or both of the two zOT receptors, and show promise for future explorations of the anatomy and evolution of networks underlying social behaviour.
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| 7. |
- Radomska, Katarzyna J., et al.
(författare)
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Characterization and Expression of the Zebrafish qki Paralogs
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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