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GSE17994
Mus musculus
19 Downloadable Samples
Description
Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester, CCI-779, improves motor performance in a transgenic mouse model of SCA3. CCI-779 inhibits mammalian target of rapamycin (mTOR) and hence upregulates protein degradation by autophagy. CCI-779 reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. CCI-779 is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of SCA3. Using this disease model and treatment paradigm we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of SCA3. This approach identified Usp15, which showed expression changes at both the mRNA and protein level. Usp15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalised following CCI-779 treatment, as the number of transcripts changed was low and the magnitude of these changes was small we suggest that transcriptional dysregulation may not be an important step in the primary pathogenesis of SCA3.
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No associated publication
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Sex, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Periphilin is a protein which is involved in multiple processes in vivo, including terminal differentiation of keratinozytes as well as cell-cycle and cancer related functions. Here we generated mice with a targeted disruption of the periphilin-1 gene to explore its physiological role from an organismic perspective. In accordance with a ubiquitous expression of periphilin in the murine embryo, the homozygous deficiency of periphilin is lethal in early embryogenesis. We therefore characterized mice with a disruption of only one periphilin allele. As heterozygous periphilin knockout mice show no obvious histological alterations and have no apparent behavioural phenotypes, we compared whole transcriptome RNA expression profiles of total brain tissue of periphilin+/- knockout mice and wild type littermates for an in-depth analysis of heterozygous animals. In periphilin+/- knockout mice, 3 probe sets were indicative of significant differential expression (p 0.05, SLR 1 which is equivalent to 2 fold). Two of these probe sets (1438864_at and 1439170_at) refer to unannotated or unclassifiable genes. According to the NetAffx Analysis Center, the third probe set (1447831_s_at) is assigned to myotubularin related protein 7 (Mtmr7). The probe set, however, lies upstream of the Mtmr7 gene (Ensembl gene ENSMUSG00000039431), and its signal is therefore not representative for the Mtmr7 gene. Quantitative RT-PCR (qRT-PCR) analysis with a primer set specific for Mtmr7 confirmed that its expression is not altered in periphilin+/- knockout mice (relative expression compared to wild type: 0.924; p = 0.419). In summary, none of more than 45.000 covered transcripts is differentially expressed in periphilin+/- knockout mice in comparison to wild type littermates.
Publication Title
No associated publication
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No sample metadata fields
View Samples- Mus musculus
- 80 Downloadable Samples
Description
Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of -synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Thus, aging Pink1/ mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death. Transcriptome microarray data of Pink1-/- mouse brains in absence of a stressor, even at old age, show remarkably sparse dysregulations. See Gispert-S et al 2009 PLOS ONE.
Publication Title
Potentiation of neurotoxicity in double-mutant mice with Pink1 ablation and A53T-SNCA overexpression.
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Age, Specimen part
View Samples- Mus musculus
- 67 Downloadable Samples
Description
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder, which is caused by an unstable CAG-repeat expansion in the SCA2 gene, that encodes a polyglutamine tract (polyQ-tract) expansion in ataxin-2 protein (ATXN2). The RNA-binding protein ATXN2 interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum or to polysomes. Under cell stress ATXN2 and PABPC1 show redistribution to stress granules where mRNAs are kept away from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates their processing. Here, we investigated Atxn2 knock-out (Atxn2-/-) mouse liver, cerebellum and midbrain regarding their RNA profile, employing oligonucleotide microarrays for screening and RNA deep sequencing for validation. Modest ~1.4-fold upregulations were observed for the level of many mRNAs encoding ribosomal proteins and other translation pathway factors. Quantitative reverse transcriptase PCR and immunoblots in liver tissue confirmed these effects and demonstrated an inverse correlation also with PABPC1 mRNA and protein. ATXN2 deficiency also enhanced phosphorylation of the ribosomal protein S6, while impairing the global protein synthesis rate, suggesting a block between the enhanced translation drive and the impaired execution. Furthermore, ATXN2 overexpression and deficiency retarded cell cycle progression. ATXN2 mRNA levels showed a delayed phasic twofold increase under amino acid and serum starvation, similar to ATXN3, but different from motor neuron disease genes MAPT and SQSTM1. ATXN2 mRNA levels depended particularly on mTOR signalling. Altogether the data implicate ATXN2 in the adaptation of mRNA translation and cell growth to nutrient availability and stress.
Publication Title
Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate.
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Age, Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
Description
Alpha-synuclein is an abundant protein implicated in synaptic function and plasticity, but the molecular mechanism of its action is not understood. Missense mutations and gene duplication/triplication events result in Parkinson's disease, a neurodegenerative disorder of old age with impaired movement and emotion control. Here, we systematically investigated the striatal as well as the cerebellar transcriptome profile of alpha-synuclein-deficient mice via a genome-wide microarray survey in order to gain hypothesis-free molecular insights into the physiological function of alpha-synuclein. A genotype-dependent, specific and strong downregulation of forkhead box P1 (Foxp1) transcript levels was observed in all brain regions from postnatal age until old age and could be validated by qPCR. In view of the co-localization and heterodimer formation of FOXP1 with FOXP2, a transcription factor with a well established role for vocalization, and the reported regulation of both alpha-synuclein and FOXP2 expression during avian song learning, we performed a detailed assessment of mouse movements and vocalizations in the postnatal period. While there was no difference in isolation-induced behavioral activity in these animals, the alpha-synuclein-deficient mice exhibited an increased production of isolation-induced ultrasonic vocalizations (USVs). This phenotype might also reflect the reduced expression of the anxiety-related GABA-A receptor subunit gamma 2 (Gabrg2) we observed. Taken together, we identified an early behavioral consequence of alpha-synuclein deficiency and accompanying molecular changes, which supports the notion that the neural connectivity of sound or emotion control systems is affected.
Publication Title
Alpha-synuclein deficiency affects brain Foxp1 expression and ultrasonic vocalization.
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Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Dppa4 (Developmental pluripotency-associated 4) has been identified in several highprofile screens as a gene that is expressed exclusively in pluripotent cells. It encodes a nuclear protein with a SAP-like domain and appears to be associated preferentially with transcriptionally active chromatin. Its exquisite expression pattern and results of RNA interference experiments have led to speculation that Dppa4, as well as its nearby homolog Dppa2, might play essential roles in embryonic stem cell function and/or germ cell development. To rigorously assess suggested roles, we have generated Dppa4-deficient and Dppa4/Dppa2 double-deficient ES cells, as well as mice lacking Dppa4. Contrary to predictions, we find that Dppa4 is completely dispensable for ES cell identity and germ cell development. Instead, loss of Dppa4 in mice results in late embryonic/peri-natal death and striking skeletal defects with partial penetrance. Thus, surprisingly, Dppa4-deficiency affects tissues, which never transcribed the gene, and at least some loss-of-function defects manifest phenotypically at an embryonic stage long after physiologic Dppa4 expression has ceased. Concomitant with targeted gene inactivation, we have introduced into the Dppa4 locus a red fluorescent marker (tandem-dimer RFP), which is compatible with GFP-based proteins and allows non-invasive visualization of pluripotent cells and reprogramming events.
Publication Title
The pluripotency-associated gene Dppa4 is dispensable for embryonic stem cell identity and germ cell development but essential for embryogenesis.
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Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 54 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Exploiting microRNA and mRNA profiles generated in vitro from carcinogen-exposed primary mouse hepatocytes for predicting in vivo genotoxicity and carcinogenicity.
Alternate Accession IDs
Sample Metadata Fields
Specimen part, Compound
View Samples- Mus musculus, Homo sapiens
- 94 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Integrating factor analysis and a transgenic mouse model to reveal a peripheral blood predictor of breast tumors.
Alternate Accession IDs
Sample Metadata Fields
Specimen part
View Samples- Mus musculus, Homo sapiens
- 231 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer.
Alternate Accession IDs
Sample Metadata Fields
Sex, Age, Disease stage, Race
View Samples- Mus musculus
- 54 Downloadable Samples
Description
The well-defined battery of in vitro systems applied within chemical cancer risk assessment is often characterised by a high false-positive rate, thus repeatedly failing to correctly predict the in vivo genotoxic and carcinogenic properties of test compounds. Toxicogenomics, i.e. mRNA-profiling, has been proven successful in improving the prediction of genotoxicity in vivo and the understanding of underlying mechanisms. Recently, microRNAs have been discovered as post-transcriptional regulators of mRNAs. It is thus hypothesised that using microRNA response-patterns may further improve current prediction methods. This study aimed at predicting genotoxicity and non-genotoxic carcinogenicity in vivo, by comparing microRNA- and mRNA-based profiles, using a frequently applied in vitro liver model and exposing this to a range of well-chosen prototypical carcinogens. Primary mouse hepatocytes (PMH) were treated for 24 and 48h with 21 chemical compounds [genotoxins (GTX) vs. non-genotoxins (NGTX) and non-genotoxic carcinogens (NGTX-C) versus non-carcinogens (NC)]. MicroRNA and mRNA expression changes were analysed by means of Exiqon and Affymetrix microarray-platforms, respectively. Classification was performed by using Prediction Analysis for Microarrays (PAM). Compounds were randomly assigned to training and validation sets (repeated 10 times). Before prediction analysis, pre-selection of microRNAs and mRNAs was performed by using a leave-one-out t-test. No microRNAs could be identified that accurately predicted genotoxicity or non-genotoxic carcinogenicity in vivo. However, mRNAs could be detected which appeared reliable in predicting genotoxicity in vivo after 24h (7 genes) and 48h (2 genes) of exposure (accuracy: 90% and 93%, sensitivity: 65% and 75%, specificity: 100% and 100%). Tributylinoxide and para-Cresidine were misclassified. Also, mRNAs were identified capable of classifying NGTX-C after 24h (5 genes) as well as after 48h (3 genes) of treatment (accuracy: 78% and 88%, sensitivity: 83% and 83%, specificity: 75% and 93%). Wy-14,643, phenobarbital and ampicillin trihydrate were misclassified. We conclude that genotoxicity and non-genotoxic carcinogenicity probably cannot be accurately predicted based on microRNA profiles. Overall, transcript-based prediction analyses appeared to clearly outperform microRNA-based analyses.
Publication Title
Exploiting microRNA and mRNA profiles generated in vitro from carcinogen-exposed primary mouse hepatocytes for predicting in vivo genotoxicity and carcinogenicity.
Alternate Accession IDs
Sample Metadata Fields
Specimen part, Compound
View Samples