| 1. |
- Corell, Mikael, et al.
(författare)
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GABA and its B-receptor are present at the node of Ranvier in a small population of sensory fibers, implicating a role in myelination
- 2015
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Ingår i: Journal of Neuroscience Research. - : Wiley. - 0360-4012 .- 1097-4547. ; 93:2, s. 285-295
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Tidskriftsartikel (refereegranskat)abstract
- The γ-aminobutyric acid (GABA) type B receptor has been implicated in glial cell development in the peripheral nervous system (PNS), although the exact function of GABA signaling is not known. To investigate GABA and its B receptor in PNS development and degeneration, we studied the expression of the GABAB receptor, GABA, and glutamic acid decarboxylase GAD65/67 in both development and injury in fetal dissociated dorsal root ganglia (DRG) cell cultures and in the rat sciatic nerve. We found that GABA, GAD65/67, and the GABAB receptor were expressed in premyelinating and nonmyelinating Schwann cells throughout development and after injury. A small population of myelinated sensory fibers displayed all of these molecules at the node of Ranvier, indicating a role in axon-glia communication. Functional studies using GABAB receptor agonists and antagonists were performed in fetal DRG primary cultures to study the function of this receptor during development. The results show that GABA, via its B receptor, is involved in the myelination process but not in Schwann cell proliferation. The data from adult nerves suggest additional roles in axon-glia communication after injury.
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| 2. |
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| 3. |
- 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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| 4. |
- Olszewski, Pawel K., et al.
(författare)
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Fto colocalizes with a satiety mediator oxytocin in the brain and upregulates oxytocin gene expression
- 2011
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 408:3, s. 422-426
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Tidskriftsartikel (refereegranskat)abstract
- Single nucleotide polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. Alterations in Fto expression in transgenic animals affect body weight, energy expenditure and food intake. Fto, a nuclear protein and proposed transcription co-factor, has been speculated to affect energy balance through a functional relationship with specific genes encoding feeding-related peptides. Herein, we employed double immunohistochemistry and showed that the majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto in the brain of male and female mice. We then overexpressed Fto in a murine hypothalamic cell line and, using qPCR, detected a 50% increase in the level of oxytocin mRNA. Expression levels of several other feeding-related genes, including neuropeptide V (NPY) and Agouti-related protein (AgRP), were unaffected by the FTO transfection. Addition of 10 and 100 nmol oxytocin to the cell culture medium did not affect Fto expression in hypothalamic cells. We conclude that Fto, a proposed transcription co-factor, influences expression of the gene encoding a satiety mediator, oxytocin.
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| 5. |
- Olszewski, Pawel K., et al.
(författare)
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Fto immunoreactivity is widespread in the rodent brain and abundant in feeding-related sites, but the number of Fto-positive cells is not affected by changes in energy balance
- 2011
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Ingår i: Physiology and Behavior. - : Elsevier BV. - 0031-9384 .- 1873-507X. ; 103:2, s. 248-253
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Tidskriftsartikel (refereegranskat)abstract
- A single nucleotide polymorphism in the FTO gene is associated with obesity in humans. Evidence gathered in animals mainly relates energy homeostasis to the central FTO mRNA levels, but our knowledge of the Fto protein distribution and regulation is limited. Fto, a demethylase and transcriptional coactivator, is thought to regulate expression of other genes. Herein, we examined Fto immunoreactivity (IR) in the mouse and rat brain with emphasis on sites governing energy balance. We also studied whether energy status affects central Fto IR. We report that Fto IR, limited to nuclear profiles, is widespread in the brain, in- and outside feeding circuits; it shows a very similar distribution in feeding-related sites in mice and rats. Several areas regulating energy homeostasis display enhanced intensity of Fto staining: the arcuate, paraventricular, supraoptic, dorsomedial, ventromedial nuclei, and dorsal vagal complex. Some regions mediating feeding reward, including the bed nucleus of the stria terminalis, have ample Fto IR. We found that differences in energy status between rats fed ad libitum, deprived or refed following deprivation, did not affect the number of Fto-positive nuclei in 10 sites governing consumption for energy or reward. We conclude that Fto IR, widespread in the rodent brain, is particularly abundant in feeding circuits, but the number of Fto-positive neurons is unaffected by changes in energy balance.
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| 6. |
- Olszewski, Pawel K, et al.
(författare)
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Hypothalamic FTO is associated with the regulation of energy intake not feeding reward
- 2009
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 10, s. 129-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Polymorphism in the FTO gene is strongly associated with obesity, but little is known about the molecular bases of this relationship. We investigated whether hypothalamic FTO is involved in energy-dependent overconsumption of food. We determined FTO mRNA levels in rodent models of short- and long-term intake of palatable fat or sugar, deprivation, diet-induced increase in body weight, baseline preference for fat versus sugar as well as in same-weight animals differing in the inherent propensity to eat calories especially upon availability of diverse diets, using quantitative PCR. FTO gene expression was also studied in organotypic hypothalamic cultures treated with anorexigenic amino acid, leucine. In situ hybridization (ISH) was utilized to study FTO signal in reward- and hunger-related sites, colocalization with anorexigenic oxytocin, and c-Fos immunoreactivity in FTO cells at initiation and termination of a meal. RESULTS: Deprivation upregulated FTO mRNA, while leucine downregulated it. Consumption of palatable diets or macronutrient preference did not affect FTO expression. However, the propensity to ingest more energy without an effect on body weight was associated with lower FTO mRNA levels. We found that 4-fold higher number of FTO cells displayed c-Fos at meal termination as compared to initiation in the paraventricular and arcuate nuclei of re-fed mice. Moreover, ISH showed that FTO is present mainly in hunger-related sites and it shows a high degree of colocalization with anorexigenic oxytocin. CONCLUSION: We conclude that FTO mRNA is present mainly in sites related to hunger/satiation control; changes in hypothalamic FTO expression are associated with cues related to energy intake rather than feeding reward. In line with that, neurons involved in feeding termination express FTO. Interestingly, baseline FTO expression appears linked not only with energy intake but also energy metabolism.
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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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| 8. |
- 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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| 9. |
- 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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