| 1. |
- Jazin, Elena, et al.
(författare)
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Sex differences in molecular neuroscience : from fruit flies to humans
- 2010
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Ingår i: Nature Reviews Neuroscience. - : Springer Science and Business Media LLC. - 1471-003X .- 1471-0048. ; 11:1, s. 9-17
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Forskningsöversikt (refereegranskat)abstract
- A plethora of discoveries relating to sex influences on brain function is rapidly moving this field into the spotlight for most areas of neuroscience. The domain of molecular or genetic neuroscience is no exception. The goal of this article is to highlight key developments concerning sex-based dimorphisms in molecular neuroscience, describe control mechanisms regulating these differences, address the implications of these dimorphisms for normal and abnormal brain function and discuss what these advances mean for future work in the field. The overriding conclusion is that, as for neuroscience in general, molecular neuroscience has to take into account potential sex influences that might modify signalling pathways.
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| 2. |
- Jiang, Lin, et al.
(författare)
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QKI-7 regulates expression of interferon-related genes in human astrocyte glioma cells
- 2010
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:9, s. e13079-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The human QKI gene, called quaking homolog, KH domain RNA binding (mouse), is a candidate gene for schizophrenia encoding an RNA-binding protein. This gene was shown to be essential for myelination in oligodendrocytes. QKI is also highly expressed in astrocytes, but its function in these cells is not known. METHODS/PRINCIPAL FINDINGS: We studied the effect of small interference RNA (siRNA)-mediated QKI depletion on global gene expression in human astrocyte glioma cells. Microarray measurements were confirmed with real-time quantitative polymerase chain reaction (qPCR). The presence of QKI binding sites (QRE) was assessed by a bioinformatic approach. Viability and cell morphology were also studied. The most significant alteration after QKI silencing was the decreased expression of genes involved in interferon (IFN) induction (P = 6.3E-10), including IFIT1, IFIT2, MX1, MX2, G1P2, G1P3, GBP1 and IFIH1. All eight genes were down-regulated after silencing of the splice variant QKI-7, but were not affected by QKI-5 silencing. Interestingly, four of them were up-regulated after treatment with the antipsychotic agent haloperidol that also resulted in increased QKI-7 mRNA levels. CONCLUSIONS/SIGNIFICANCE: The coordinated expression of QKI-7 splice variant and IFN-related genes supports the idea that this particular splice variant has specific functions in astrocytes. Furthermore, a role of QKI-7 as a regulator of an inflammatory gene pathway in astrocytes is suggested. This hypothesis is well in line with growing experimental evidence on the role of inflammatory components in schizophrenia.
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| 3. |
- Lee, Iwa, 1986-
(författare)
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Developmental Neurotoxicity of Environmental Pollutants : Effects on neuronal protein markers after neonatal exposure
- 2013
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focused on investigations of the developmental neurotoxic effects of bisphenol A (BPA) or perfluorohexane sulfonate (PFHxS), after a single neonatal exposure, during a critical period of the brain development in mice.BPA is a well-known industrial chemical used in the production of polymer products and PFHxS is used as an industrial additive as a surfactant. Commonly, these two compounds have been found in the environment, wild-life and in humans. They are a cause of concern as BPA is known to be an endocrine disrupter and PFHxS is presently unregulated; although similar compounds have been phased-out of production. Additionally, humans may be exposed to these compounds throughout their life time starting already before birth. Infants and children are especially vulnerable as they are not yet fully developed and therefore can be more sensitive to toxic insults. The brain growth spurt (BGS), is a critical period of the mammalian brain development, and is characterized by a rapid growth as well as biochemical changes. Toxic insults during this period have shown to cause persistent and irreversible behavioral and cognitive dysfunctions in mice. The onset and duration of the BGS varies between species, and in mice it is postnatal starting from birth and spans up to 3-4 weeks of life. In humans, it starts from around the third trimester and extends up to the first two years of life. For both species the BGS coincide with the period of lactation. The BGS process involves several important neuroproteins, such as BDNF, CaMKII, GAP-43, synaptophysin and tau. These neuroproteins are essential for maintaining normal neuronal growth and synaptogenesis. Additionally, these proteins display specific ontogenic patterns and peak during the BGS in the neonatal mouse brain.This thesis has shown that BPA and PFHxS can cause developmental neurotoxic effects when administered directly during the peak of the BGS. BPA induced altered levels of CaMKII and synaptophysin in adult mice, whereas PFHxS induced altered levels of CaMKII, GAP-43, synaptophysin and tau in neonatal mice. These effects are similar to previously studied persistent organic pollutants such as polybrominated diphenyl ethers (PBDEs) and other perfluorinated compounds (PFCs). The altered neuroprotein levels may be a plausible explanation to recently seen disarranged behavior in adult mice neonatally exposed to BPA or PFHxS. As the two compounds are seemingly different, but produce similar neurotoxic effect, it further supports the notion that the developing brain is sensitive to toxic insults when exposed during a sensitive period of brain development. Also, further investigations on finding mechanisms of action and biomarkers for toxic insult of environmental pollutants are important in order to be able to foresee and prevent future consequences of existing and new emerging substances.
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| 4. |
- Radomska, Katarzyna, 1984-
(författare)
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Functional studies of the Quaking gene : Focus on astroglia and neurodevelopment
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The RNA-binding protein Quaking (QKI) plays a fundamental role in post-transcriptional gene regulation during mammalian nervous system development. QKI is well known for advancing oligodendroglia differentiation and myelination, however, its functions in astrocytes and embryonic central nervous system (CNS) development remain poorly understood. Uncovering the complete spectrum of QKI molecular and functional repertoire is of additional importance in light of growing evidence linking QKI dysfunction with human disease, including schizophrenia and glioma. This thesis summarizes my contribution to fill this gap of knowledge. In a first attempt to identify the QKI-mediated molecular pathways in astroglia, we studied the effects of QKI depletion on global gene expression in the human astrocytoma cell line. This work revealed a previously unknown role of QKI in regulating immune-related pathways. In particular, we identified several putative mRNA targets of QKI involved in interferon signaling, with possible implications in innate cellular antiviral defense, as well as tumor suppression. We next extended these investigations to human primary astrocytes, in order to more accurately model normal brain astrocytes. One of the most interesting outcomes of this analysis was that QKI regulates expression of transcripts encoding the Glial Fibrillary Acidic Protein, an intermediate filament protein that mediates diverse biological functions of astrocytes and is implicated in numerous CNS pathologies. We also characterized QKI splice variant composition and subcellular expression of encoded protein isoforms in human astrocytes. Finally, we explored the potential use of zebrafish as a model system to study neurodevelopmental functions of QKI in vivo. Two zebrafish orthologs, qkib and qki2, were identified and found to be widely expressed in the CNS neural progenitor cell domains. Furthermore, we showed that a knockdown of qkib perturbs the development of both neuronal and glial populations, and propose neural progenitor dysfunction as the primary cause of the observed phenotypes. To conclude, the work presented in this thesis provides the first insight into understanding the functional significance of the human QKI in astroglia, and introduces zebrafish as a novel tool with which to further investigate the importance of this gene in neural development.
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| 5. |
- Radomska, Katarzyna J., et al.
(författare)
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RNA-binding protein QKI regulates Glial fibrillary acidic protein expression in human astrocytes
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:7, s. 1373-1382
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Tidskriftsartikel (refereegranskat)abstract
- Linkage, association and expression studies previously pointed to the human QKI, KH domain containing, RNA-binding (QKI) as a candidate gene for schizophrenia. Functional studies of the mouse orthologue Qk focused mainly on its role in oligodendrocyte development and myelination, while its function in astroglia remained unexplored. Here, we show that QKI is highly expressed in human primary astrocytes and that its splice forms encode proteins targeting different subcellular localizations. Uncovering the role of QKI in astrocytes is of interest in light of growing evidence implicating astrocyte dysfunction in the pathogenesis of several disorders of the central nervous system. We selectively silenced QKI splice variants in human primary astrocytes and used RNA sequencing to identify differential expression and splice variant composition at the genome-wide level. We found that an mRNA expression of Glial fibrillary acidic protein (GFAP), encoding a major component of astrocyte intermediate filaments, was down-regulated after QKI7 splice variant silencing. Moreover, we identified a potential QKI-binding site within the 3 untranslated region of human GFAP. This sequence was not conserved between mice and humans, raising the possibility that GFAP is a target for QKI in humans but not rodents. Haloperidol treatment of primary astrocytes resulted in coordinated increases in QKI7 and GFAP expression. Taken together, our results provide the first link between QKI and GFAP, two genes with alterations previously observed independently in schizophrenic patients. Our findings for QKI, together with its well-known role in myelination, suggest that QKI is a hub regulator of glia function in humans.
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| 6. |
- Reinius, Björn, et al.
(författare)
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Abundance of female-biased and paucity of male-biased somatically expressed genes on the mouse X-chromosome.
- 2012
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Ingår i: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Background: Empirical evaluations of sexually dimorphic expression of genes on the mammalian X-chromosome are needed to understand the evolutionary forces and the gene-regulatory mechanisms controlling this chromosome. We performed a large-scale sex-bias expression analysis of genes on the X-chromosome in six different somatic tissues from mouse. Results: Our results show that the mouse X-chromosome is enriched with female-biased genes and depleted of male-biased genes. This suggests that feminisation as well as de-masculinisation of the X-chromosome has occurred in terms of gene expression in non-reproductive tissues. Several mechanisms may be responsible for the control of female-biased expression on chromosome X, and escape from X-inactivation is a main candidate. We confirmed escape in case of Tmem29 using RNA-FISH analysis. In addition, we identified novel female-biased non-coding transcripts located in the same female-biased cluster as the well-known coding X-inactivation escapee Kdm5c, likely transcribed from the transition-region between active and silenced domains. We also found that previously known escapees only partially explained the overrepresentation of female-biased X-genes, particularly for tissue-specific female-biased genes. Therefore, the gene set we have identified contains tissue-specific escapees and/or genes controlled by other sexually skewed regulatory mechanisms. Analysis of gene age showed that evolutionarily old X-genes (>100 myr, preceding the radiation of placental mammals) are more frequently female-biased than younger genes. Conclusion: Altogether, our results have implications for understanding both gene regulation and gene evolution of mammalian X-chromosomes, and suggest that the final result in terms of the X-gene composition (masculinisation versus feminisation) is a compromise between different evolutionary forces acting on reproductive and somatic tissues.
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| 7. |
- Reinius, Björn, et al.
(författare)
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Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse
- 2010
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 11:1, s. 614-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sexual dimorphism in brain gene expression has been recognized in several animal species.However, the relevant regulatory mechanisms remain poorly understood. To investigatewhether sex-biased gene expression in mammalian brain is globally regulated or locallyregulated in diverse brain structures, and to study the genomic organisation of brain-expressedsex-biased genes, we performed a large scale gene expression analysis of distinct brainregions in adult male and female mice. Results: This study revealed spatial specificity in sex-biased transcription in the mouse brain, andidentified 173 sex-biased genes in the striatum; 19 in the neocortex; 12 in the hippocampusand 31 in the eye. Genes located on sex chromosomes were consistently over-represented inall brain regions. Analysis on a subset of genes with sex-bias in more than one tissue revealedY-encoded male-biased transcripts and X-encoded female-biased transcripts known to escapeX-inactivation. In addition, we identified novel coding and non-coding X-linked genes withfemale-biased expression in multiple tissues. Interestingly, the chromosomal positions of allof the female-biased non-coding genes are in close proximity to protein-coding genes thatescape X-inactivation. This defines X-chromosome domains each of which contains a codingand a non-coding female-biased gene. Lack of repressive chromatin marks in non-codingtranscribed loci supports the possibility that they escape X-inactivation. Moreover, RNADNAcombined FISH experiments confirmed the biallelic expression of one such noveldomain. Conclusion: This study demonstrated that the amount of genes with sex-biased expression variesbetween individual brain regions in mouse. The sex-biased genes identified are localized onmany chromosomes. At the same time, sexually dimorphic gene expression that is common toseveral parts of the brain is mostly restricted to the sex chromosomes. Moreover, the studyuncovered multiple female-biased non-coding genes that are non-randomly co-localized onthe X-chromosome with protein-coding genes that escape X-inactivation. This raises thepossibility that expression of long non-coding RNAs may play a role in modulating geneexpression in domains that escape X-inactivation in mouse.
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| 8. |
- Reinius, Björn
(författare)
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Sexually Dimorphic Gene Expression in the Mammalian Brain
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In recent times, major advances have been made towards understanding sexual dimorphism in the brain on a molecular basis. This thesis summarises my modest contributions to these endeavours. Sexual dimorphisms are manifested throughout the spectrum of biological complexity, and can be studied by numerous approaches. The approach of this thesis is to explore sex-biased gene expression in mammalian somatic tissues. Paper I describes an evolutionarily conserved sexual gene expression pattern in the primate brain. Conserved sex-biased genes may underlie important sex differences in neurobiology. In Paper II, Y-chromosome genes expressed across several regions of the human male brain during mid-gestation are identified. Such genes may play male-specific roles during brain development. The studies of Papers III and IV explore sex-biased gene expression in several somatic tissues from mouse. The amount of genes with sex-biased expression varied in different brain regions. The striatum was particularly interesting, with an order of magnitude increase in the number of sex-biased genes as compared to the other included brain regions. Of potentially wider significance are my observations regarding the transcriptional regulation of domains that escape X-chromosome inactivation (XCI). Specifically, I provide the first evidence that long non-coding RNAs (lncRNAs) transcribe together with protein-coding genes in XCI-escaping domains. This raises the possibility that lncRNAs mediate the transcriptional regulation of XCI-escaping domains. I also present evidence that the mouse X-chromosome has undergone both feminisation and de-masculinisation during evolution, as indicated by the sex-skewed regulation of genes on this chromosome. This finding is relevant for understanding the selective forces that shaped the mammalian X-chromosome. In the final chapter, Paper V, the generation of a novel transgenic mouse line, Gpr101-Cre, is described. Its progeny can be used for functional studies of striatum, a brain structure with major sexual dimorphism, as is further demonstrated in the Papers of this thesis.
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| 9. |
- Saetre, P., et al.
(författare)
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Age-Related Changes in Gene Expression are Accelerated in Alzheimer's Disease
- 2011
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Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 65:9, s. 971-974
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Tidskriftsartikel (refereegranskat)abstract
- In the normal brain, age is associated with changes in gene expression. Age is also a prominent risk factor for Alzheimer's disease (AD), where clinical features are similar to age-related decreases in cognitive performance. We hypothesized that some age-related changes in gene expression are accelerated in AD patients. To study this, we selected 10 candidate genes earlier shown by microarray analysis to be differentially expressed in AD (Emilsson et al., [2006] Neurobiol Dis 21:618-625). Using real-time PCR analysis and a control based statistical model, we investigated age-related changes in mRNA levels in a large collection of human brain postmortem tissues from AD patients and controls. Our results demonstrate that the age-related changes in gene expression are manifested earlier in AD. Furthermore, five of the genes (ITPKB, RGS4, RAB3A, STMN1, SYNGR3) have in common an involvement in neuronal calcium dependent signaling, a cellular process previously related to both AD and aging. These observations suggest that coordinated transcriptional changes associated with ageing and calcium homeostasis in the human brain are accelerated in patients with AD. Our results point to the possibility that the activity of these genes can be used in the future as a palette of biomarkers for predicting disease risk in young individuals.
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| 10. |
- Wirén, Anders, 1977-
(författare)
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Correlated selection responses in animal domestication : the behavioural effects of a growth QTL in chickens
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Studying animal domestication offers an opportunity to understand the mechanisms of evolution. Domestication is associated with a change in selection pressures; selection for production traits is introduced, and animals are faced with larger and denser social groups. It is not unexpected then that domestication produces a simultaneous change in a number of traits, both physiological and behavioural. This correlated change in traits, e.g. egg production and social behaviour has been termed the “domestic phenotype”. However, it has been shown that selection for one trait alone among the many associated with the domestic phenotype can lead to simultaneous changes in others. This may be a result of such traits being inherited together because of pleiotropy or close linkage of several genes affecting different traits. A chicken growth QTL has previously been found in an intercross between White Leghorn layers (WL) and their main wild ancestor, the red junglefowl (RJF). This QTL has also been found to influence explorative and social behaviours. This thesis aims to characterize this QTL further with respect to social and emotional behaviours, and tries to clarify whether pleiotropy or linkage is responsible for the many observed effects. This is done using behavioural phenotyping, genetic marker genotyping, QTL- and gene expression analysis of an intercross line between RJF and WL, and to some extent of the parental RJF and WL lines themselves. The results show that domestication in these chickens has led to increased social tolerance to unfamiliar conspecifics and a tendency to a decrease in the propensity of chickens to explore the environment, and that these effects are partly explained by the previously described growth QTL. The results also indicate that close linkage of genes, rather than pleiotropy, may be responsible for the multiple effect of the QTL, as different traits to some extent seem to be influenced by different areas within the larger QTL region. This information, in combination with that of other studies and with existing and upcoming genetic research techniques, may be used in the design of future breeding programs that take animal behaviour and welfare as well as production traits into account. Findings like these may also be of use in directing research in human psychiatric genetics.
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