Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA147387 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Genome-wide mRNA expression in brains of wild-type and eIF2B-R132H/R132H mutant mice (Geva et al., BRAIN 133 (8), 2010) profiled at postnatal (P) days 1, 18 and 21 to reflect the early proliferative stage prior to white matter establishment (P1) and the peak of oligodendrocye differentiation and myelin synthesis (P18 and P21). 3 biological replicates (whole brain without the cerebellum) from each wild-type and eIF2B-R132H/R132H mutant mice at 3 postnatal (P) days 1, 18 and 21 were used for RNA extraction and hybridization on Affymetrix microarrays.
2011-11-14 | E-GEOD-32201 | biostudies-arrayexpress
Project description:Genome-wide mRNA expression in brains of wild-type and eIF2B-R132H/R132H mutant mice (Geva et al., BRAIN 133 (8), 2010) profiled at postnatal (P) days 1, 18 and 21 to reflect the early proliferative stage prior to white matter establishment (P1) and the peak of oligodendrocye differentiation and myelin synthesis (P18 and P21).
2011-11-14 | GSE32201 | GEO
Project description:eIF2B is a master regulator of translation initiation and mediator of the integrated stress response (ISR). Partial-loss-of function mutations are associated with eIF2B-leukodystrophy termed Vanishing White Matter Disease (VWMD), a recessive neurodegenerative disorder. Astrocytes, the brain homeostasis keepers, are central to VWMD owing to their hyper-sensitivity to eIF2B activity, as manifested by their phenotypic deficits due to the mutation. Here we used astrocytes isolated from the brains of WT and eIF2B5R132H/R132H mice to assess their transcriptome and translatome responses upon cytokine-mediated activation, an mTOR-driven process critical for brain homeostasis. We found that: (i) a mild eIF2B mutation has the power to disrupt translation regulation programs involving ~30% of the expressed genes; (ii) a common compensatory strategy to overcome the translation regulation failure is manipulation of mRNA abundance; and (iii) dysregulation of functionally related genes can be used to reliably predict deficits of corresponding cellular functions. Specifically, the study illuminates the molecular anomalies responsible for the impaired ribogenesis and mitochondrial respiration of eIF2B-mutant astrocytes. Moreover, it reliably predicts, for the first time, impaired cholesterol biosynthesis in eIF2B-mutant astrocytes. This work demonstrates the strength of combined transcriptome/translatome approach to decipher links between mild expression anomalies and downstream cellular defects associated with VWMD.
2025-03-19 | GSE252362 | GEO
Project description:Eukaryotic translation initiation factor 2B is a master regulator of protein synthesis under normal and stress conditions. Mutations in any of the five genes encoding its subunits lead to Vanishing White Matter (VWM) disease, a recessive genetic deadly illness caused by progressive loss of white matter in the brain. Although fibroblasts are not involved in the disease, we used mouse embryo fibroblasts (MEFs) isolated from Eif2b5R132H/R132H mice to demonstrate their compromised mitochondrial translation, unbalanced stoichiometry of proteins involved in oxidative phosphorylation, decreased basal and maximal oxygen consumption rate, and increased mitochondrial abundance reflecting adaptation to meet energy requirements. The involvement of eIF2B in mitochondrial function and abundance was validated in primary astrocytes isolated from Eif2b5R132H/R132H mice brains. We found that oxidative respiration deficiency is more robust in astrocytes and does not reach normal cellular levels even following 2-fols increase in mitochondrial content. The consequent increase in basal and maximal glycolysis in mutant astrocytes demonstrates their enhanced sensitivity to the impaired oxidative phosphorylation, illuminating the importance of mitochondrial function in VWM pathology. The data demonstrates the critical role of eIF2B in tight coordination of expression from nuclear and mitochondrial genomes. Further dissection of the signalling network associated with eIF2B function will help generating therapeutic strategies for VWM disease and possibly other neurodegenerative disorders.
2017-07-11 | PXD005854 | Pride
Project description:The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. We have characterized an eIF2B loss of function (LOF) mouse model, carrying the homozygous Eif2b5[R191H] mutation that is homologous to the Vanishing White Matter Disease (VWMD)-causing human R195H variant. Characterization of previously reported transcript markers in animals 3-4 weeks of age confirmed ISR activation in the brain, but not in heterozygous or wild-type littermates.The robust elevation of ISR markers was further confirmed in bulk brain RNA sequencing analysis of a separate cohort of homozygous mutants and wild-type littermates. Known ATF4 targets feature prominently among the most strongly up-regulated genes in the eIF2B mutant compared to WT littermates.
2023-08-22 | GSE240150 | GEO
Project description:Arid1b is a chromatin remodeler implicated in neurodevelopmental disorders. Arid1b mutant mice with haploinsufficiency (Arid1b HT) displayed persistent excitatory synaptic dysfunction from juvenile to adult stage, decreased synaptic density and transmission. Moreover, they showed autistic-like behaviors in both of early and adult stages, decreased sociability in pup USV calling and adult social interaction, and adult repetitive grooming. To investigate early transcriptomic changes in Arid1b mutant mice, RNAseq analysis of whole brain from wild-type and Arid1b mutant mice at postnatal day 10 was done. Transcriptomic changes support these electrophysiological and behavioral deficits. Arid1b HT mice at postnatal day 10 showed alterations in genes implicated in synaptic functions and ASD. Next, we found that early chronic fluoxetine treatment could carry out long-lasting restoration in electrophysiological and behavioral deficits in Arid1b HT mice. Whole brain transcriptomic analysis with mice at postnatal day 120 which underwent chronic fluoxetine treatment from postnatal day 3 to postnatal day 21 via mammillary milk was done to figure out transcriptomic reprogramming which contributes to this restoration. Comparing fluoxetine treated Arid1b HT mice and vehicle group, fluoxetine treated mice showed upregulation of synapse-related genes and disease related gene sets with reverse-ASD directions.
2022-07-21 | GSE189653 | GEO
Project description:Microglia play critical roles in the maturation and refinement of neural networks of the developing brain. The goal of this study was to investigate the role of microglial STAT3 in postnatal brain development. This experiment was aimed to determine gene profiles (RNA-seq) of wild-type and Stat3 mutant microglia. Cx3cr1CreERT2/+:Stat3loxP mice were generated to achieve tamoxifen-inducible deletion of exon 22 of the Stat3 gene in microglia. mRNA was prepared from acutely isolated microglia from postnatal day 8 (P8) pups that received tamoxifen from postnatal day 1 to 3. Overall, we found that Stat3 mutant produced signficantly higher levels of inlfammatory cytokines and had compromised DNA damage checkpoints.
2024-12-31 | GSE173110 | GEO
Project description:Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to neomorphic enzymatic activities and the production of oncometabolite R-2-hydroxyglutarate (2-HG), contributing to the tumorigenesis of several human cancers. It has been shown that fatty acid biosynthesis is required for the growth of IDH1 mutant tumors, but the underlining mechanisms are unclear. We developed new activity-based chemical probes to study protein autopalmitoylation, and identified that the oncogenic IDH1 (R132H) mutant is uniquely autopalmitoylated at cysteine 269 (C269), which is not observed in the wild type IDH1. Molecular dynamic simulations suggest that palmitoylation of the R132H mutant could occur in a hydrophobic pocket, and enhance its dimerization, consistent with our experimental results. In addition, in vitro autopalmitoylated recombinant IDH1 mutant protein showed enhanced enzymatic activities. In cells expressing IDH1 (R132H) mutant, exogenous fatty acids enhance mutant IDH1 activities through promoting C269 autopalmitoylation, and loss of C269 palmitoylation reverses mutant-induced metabolic reprograming and hypermethylation phenotypes, and impairs cell transformation. Interestingly, a clinical IDH1 mutant inhibitor (LY3410738) strongly inhibits autopalmitoylation by binding to the lipid-binding pocket and covalently modifying C269. Our study reveals that autopalmitoylation conferred by oncogenic IDH1 R132H mutation links fatty acid metabolism to the regulation of IDH1 mutant activities, and is a druggable vulnerability of IDH1 mutant cancers.
2025-11-18 | GSE260937 | GEO
Project description:The effect of microglial STAT3 signaling on early postnatal brain development
| PRJNA723836 | ENA