The aryl hydrocarbon receptor pathway defines the time frame for restorative neurogenesis
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE121404 | GEO | 2018/10/18
REPOSITORIES: GEO
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Project description:In contrast to mammals, zebrafish has high capacity to regenerate tissue architecture and replace lost neurons after traumatic brain injury. The ependymoglia cells react to the injury and generate new neurons, which migrate to the lessoned site and contribute to the tissue restoration. Understanding molecular and cellular mechanisms underlying this regenerative neurogenesis is the crucial step towards achieving regenerative therapies in the mammalian brain. In order to identify molecular pathways governing this mode of restorative neurogenesis, we analysed changes in the transcriptome of ependymoglia cells and their progeny during regeneration process and identified Aryl hydrocarbon receptor (AhR) to be involved in regulation of ependymoglia differentiation towards post-mitotic neurons. Our in vivo imaging analysis shows that the high AhR signalling promotes direct conversion of newly identified population of ependymoglia into the post-mitotic neurons. In contrast, decrease in AhR signalling promotes ependymoglial proliferation. Interestingly, we observed inactivation of the AhR signalling shortly after the injury and return to the basal levels 7 days post injury (dpi) suggesting the role of AhR in proper timing of the direct conversion of ependymoglia, ensuring the successful repair. Taken together, we identified the role of AhR signalling pathway in regulating differentiation of ependymoglia into the neurons and setting up the proper timing of restorative neurogenesis in zebrafish brain.
2018-10-11 | GSE102400 | GEO
Project description:The aryl hydrocarbon receptor pathway defines the time frame for restorative neurogenesis
| PRJNA497264 | ENA
Project description:Wild type zebrafish (AB strain, https://zfin.org/action/genotype/view/ZDB-GENO-960809-7) were set up for mating overnight, in 3:2 ratios, females and males, respectively. Fertilized embryos from wildtype zebrafish AB strain were used for all experiments and kept in Embryo medium (E3, 5 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl2, 0.33 mM MgSO4) in an incubator at 28ºC. At 1dpf, larvae were manually dechorionated under a stereomicroscope. At 2dpf, zebrafish larvae were divided randomly into the different experimental groups, at a density of 12 larvae per well of a 12 well plate (Corning) in 1.5mL of E3. Three biological replicates of 12 larvae per condition were exposed to different conditions for 4 hours at 28 ºC: DMSO; DMSO + CH223191 (5mM); 3-o-C12-L-HSL (50mM); 3-o-C12-L-HSL (50mM) + CH223191 (5 mM ); 1-hydroxyphenazine (1-HP, 5mM); 1-HP (5mM) + CH223191(5mM) and 1-HP (5mM) + 3-o-C12-L-HSL (50mM).To mention, in experiments using the Aryl hydrocarbon Receptor inhibitor CH223191, larvae were pre-exposed to 5uM of the inhibitor for 2h prior to the start of the experiment and the inhibitor was kept during the experiment. After the desired exposure to diverse ligands, larvae were euthanized with Tricaine (MS-222, 300 µg/mL) and placed in Trizol for RNA isolation. The same experimental layout was performed 5 times, and samples were subjected to microarray hybridization and analysis.
2019-10-01 | GSE121101 | GEO
Project description:While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR-/-) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of β-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
| S-EPMC8271728 | biostudies-literature
Project description:BackgroundThe aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental agonists and dietary tryptophan metabolites for the immune response and cell cycle regulation. Emerging evidence suggests that AHR activation after acute stroke may play a role in brain ischemic injury. However, whether AHR activation alters poststroke astrogliosis and neurogenesis remains unknown.MethodsWe adopted conditional knockout of AHR from nestin-expressing neural stem/progenitor cells (AHRcKO) and wild-type (WT) mice in the permanent middle cerebral artery occlusion (MCAO) model. WT mice were treated with either vehicle or the AHR antagonist 6,2',4'-trimethoxyflavone (TMF, 5 mg/kg/day) intraperitoneally. The animals were examined at 2 and 7 days after MCAO.ResultsThe AHR signaling pathway was significantly upregulated after stroke. Both TMF-treated WT and AHRcKO mice showed significantly decreased infarct volume, improved sensorimotor, and nonspatial working memory functions compared with their respective controls. AHR immunoreactivities were increased predominantly in activated microglia and astrocytes after MCAO compared with the normal WT controls. The TMF-treated WT and AHRcKO mice demonstrated significant amelioration of astrogliosis and microgliosis. Interestingly, these mice also showed augmentation of neural progenitor cell proliferation at the ipsilesional neurogenic subventricular zone (SVZ) and the hippocampal subgranular zone. At the peri-infarct cortex, the ipsilesional SVZ/striatum, and the hippocampus, both the TMF-treated and AHRcKO mice demonstrated downregulated IL-1β, IL-6, IFN-γ, CXCL1, and S100β, and concomitantly upregulated Neurogenin 2 and Neurogenin 1.ConclusionNeural cell-specific AHR activation following acute ischemic stroke increased astrogliosis and suppressed neurogenesis in adult mice. AHR inhibition in acute stroke may potentially benefit functional outcomes likely through reducing proinflammatory gliosis and preserving neurogenesis.
| S-EPMC6790016 | biostudies-literature
Project description:Fungi, including mushrooms and mycelia, are a rich source for natural products with medicinal properties. In some cases, they can lead to opportunistic infections in humans and other mammals. In 1994, the first case of bronchopulmonary mycosis caused by the Schizophyllum commune fungus was described. Culture of the isolated specimen led to the extraction of an alkaloid compound, schizocommunin, which was more recently synthesised for biological characterization. Herein we describe schizocommunin and one of its analogues as cytotoxic against human hepatoma cells at low micromolar concentrations. Schizocommunin is shown to be a potent activator of the aryl hydrocarbon receptor (AhR) gene battery, more specifically increasing expression of the CYP1A1, CYP1B1 and UGT1A genes in human liver and lung cells. A luciferase reporter assay further confirms induction of transcription by these compounds at the xenobiotic response element. This study improves our understanding of the interaction between this fungal metabolite and xenobiotic detoxifying mechanisms in the body, and points to schizocommunin as a putative mediator of the allergic response and a useful molecule for the study of the AhR pathway.
| S-EPMC6596104 | biostudies-literature
Project description:Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.
| S-EPMC4098076 | biostudies-literature
Project description:Zebrafish larvae aryl hydrocarbon receptor ligands and inhibitor
| PRJNA495640 | ENA
Project description:VAF347 is a low molecular weight compound which inhibits allergic lung inflammation in vivo. This effect is likely due to a block of dendritic cell (DC) function to generate pro-inflammatory T-helper (Th) cells since VAF347 inhibits IL-6, CD86 and HLA-DR expression by human monocyte derived DC, three relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biological activity of VAF347 since, i) other AhR agonists display an identical activity profile in vitro, ii) gene silencing of wild type AhR expression or forced over-expression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line and iii) AhR deficient mice are resistant to the compound’s ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo. Keywords: effect of compound
2008-02-12 | GSE10463 | GEO
Project description:Histone deacetylase inhibitors (HDACI) are promising anticancer agents and their use in combination with conventional anticancer drugs is currently under investigation. We previously reported cell line-specific upregulation of ABCG2, a multidrug resistance transporter shown to control oral bioavailability and CNS penetration, by the HDACI romidepsin, although the precise mechanism in a particular cell line remains to be determined. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by numerous environmental contaminants and has been shown to be a client protein of heat shock protein 90 (Hsp90). A xenobiotic response element was defined in the ABCG2 promoter and was shown to mediate AhR signaling. Activated AhR was found to be associated with the ABCG2 promoter only in cell line models that respond to romidepsin with ABCG2 upregulation. Our data suggest that romidepsin acetylated Hsp70 and inhibited the chaperone function of Hsp90, thereby allowing the dissociation of AhR from Hsp90. The dissociation of AhR from Hsp90 may be a prerequisite for the differential upregulation of ABCG2 by romidepsin. Increasing our understanding of the mechanism(s) governing differential upregulation of ABCG2 in response to romidepsin could provide an insight into strategies needed to tackle resistance to HDACIs in cancer therapeutics.
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