Transcription profiling of spinal cord from Math1-LacZ/+ and Math1-LacZ/- E12.5 mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: George Miesegaes
PROVIDER: E-MEXP-1492 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The aim of this experiment was to determine the influence of early spinal circuit activity upon gene expression in the mouse spinal cord by comparing mRNA expression between wild-type and Munc18-1 null mice (Verhage et al., Science, 2000). RNA was extracted from the lumbar spinal cords of 4 wild-type and 4 Munc18-1 -/- littermates (2 of each genotype from 2 different litters) at E12.5, processed and hybridized to Affymetrix Mouse Gene 2.0 st arrays. The genotype of mice was determined by PCR, and validated by antibodies against Munc18-1. Mice were maintained on a C57/BL6 background. The processed data file arises from RMA processing performed using the Affymetrix Array console software.
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2015-02-09 | GSE55735 | GEO
Project description:We report the ability of the Drosha null/conditional-null mouse model to enable the identification of pri-miRNA transcripts. The conditional-null allele of Drosha phenocopies the null allele both in mESC and in mice, upon conversion to the null state with Cre. Examination of the effects of Drosha deficiency in mouse embryonic stem cells.
2015-02-09 | E-GEOD-55735 | biostudies-arrayexpress
Project description:Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (~100â??1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients. To compare the RNA Seq profiles from the cortex and spinal cord of transgenic mice expressing unexpanded human C9orf72 (F08, n=4), expanded human C9orf72 (F112, n=3/4), and nontransgenic controls (n=4).
2016-02-10 | E-GEOD-77720 | biostudies-arrayexpress
Project description:The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that M-bM-^HM-<50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesionedM-bM-^@M-^Tbut not normalM-bM-^@M-^Tadult white matter. We report that M-NM-2-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of WntM-bM-^@M-^SM-NM-2-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of M-NM-2-catenin in the oligodendrocyte lineage in vivo and (2) findings from APCMin mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated WntM-bM-^@M-^SM-NM-2-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders. 12 samples total. Two variables in the experiment: genotype (wild type or Olig2cre/DA-Cat) and Developmental stage (Day 4 or Day 15). 4 phenotypes in total with 3 biological replicates for each phenotype.
2009-12-10 | E-GEOD-19403 | biostudies-arrayexpress
Project description:Purpose: Spinal cord injury (SCI) is a devastating neurological disease without effective treatment. To generate a comprehensive view of the mechanisms involved in SCI pathology, we applied RNA-sequencing (RNA-seq) technology to characterize the temporal changes in global gene expression after contusive SCI in mice. Method Part1: A total of 27 female C57BI/6J mice (10-16 weeks of age; 20-25g; The Jackson Laboratory, Bar Harbor, ME) were used with 9 mice in each of following groups: shame control, 2 and 7 days after SCI. The surgical procedure for SCI were described previously [PMID:23289019]. Briefly, after anesthetization with a mixed solution of ketamine (80 mg/kg, ip) and xylazine (10 mg/kg, ip), mice received a dorsal laminectomy at the 9th thoracic vertebral (T9) level to expose the spinal cord and then a moderate T9 contusive injury using an Infinite Horizons impactor (PrecisionSystems and Instrumentation) at 60 kdyn with the spinestabilized using steel stabilizers inserted under the transverse processes one vertebra above and below the injury [PMID:19196178] . The shame control mice received only a dorsal laminectomy without contusive injury. Afterwards, the wound was sutured in layers, bacitracin ointment(Qualitest Pharmaceuticals,Huntsville, AL) was applied tothe wound area, 0.1mL of a 20 mg/ml stock of gentamicin(ButlerSchein, Dublin, OH) was injected subcutaneously, and the animals recovered on a water-circulating heating pad. Then mice received analgesic agent, buprenorphin(0.05 mg/kg, SQ; Reckitt Benckise, Hull, England)twice a day for two days. Bladders were manually expressed until automatic voiding returned spontaneously, which generally was within 7 days. At 2 or 7 days after SCI, the mice were anesthetized again with ketamine and xylazine and perfused briefly with normal physical saline. The injured spinal cords were then dissected and three 0.5 mm pieces of spinal cord were cut in the injured epicenter. All spinal cords were immediately frozen in liquid nitrogen and processed for RNA isolation. The spinal cords from three mice were combined into one biological replicate for RNA extraction. Three biological replicates were used. Method Part2: RNA-Seq was performed on the polyadenylated fraction of RNA isolated from tissue samples of acute (2D) and subacute phase (7D) and normal tissues (control, denoted as CTR hereafter). Three biological replicates were used for each phase.150-300 ng total RNAs were used for each sequencing library. RNA samples were polyA selected and paired-end sequencing libraries were constructed using TruSeq RNA Sample Prep Kit as described in the TruSeq RNA Sample Preparation V2 Guide (Illumina).The samples were then sequenced using the Illumina HiSeq sequencer. More than 30 million 100bp paired-end reads were generated from each biological replicate. Method Part3: Read mapping and Transcriptome construction were done by using optimized pipeline which integrate Tophat followed by Cufflinks. Result: We sequenced tissue samples from acute and subacute phases (2 days and 7 days after injury) and systematically characterized the transcriptomes with the goal of identifying pathways and genes critical in SCI pathology. The top enriched functional categories include ‘inflammation response’, ‘neurological disease’, ‘cell death and survival’ and ‘nervous system development’. The top enriched pathways include LXR/RXR Activation and Atherosclerosis Signaling etc. Furthermore, we developed a systems-based analysis framework in order to identify key determinants in the global gene networks of the acute and sub-acute phases. Some candidate genes that we identified have been shown to play important roles in SCI, which demonstrates the validity of our approach. There are also many genes whose functions in SCI have not been well studied and can be further investigated by future experiments. We have also incorporated pharmacogenomic information into our analyses. Among the genes identified, the ones with existing drug information can be readily tested in SCI animal models. Conclusion: in this study we have described an example of how global gene profiling can be translated to screening genes of interest and generating new hypotheses. Additionally, the RNA-seq enables splicing isoform identification and the estimation of expression levels, thus providing useful information for increasing the specificity of drug design and reducing potential side effect. In summary, these results provide a valuable reference data resource for a better understanding of the SCI process in the acute and sub-acute phases. mRNA profiles of Acute/subacute phase Spinal Cord Injury sample from mice were generated by RNA-sequencing using Illumina HiSeq.
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Project description:A GGGGCC repeat expansion in C9orf72 is the most common genetic cause of ALS and FTD (C9ALS/FTD). Dipeptide repeat (DPR) proteins, generated by translation of the expanded repeat, are a major pathogenic feature of C9ALS/FTD pathology, but their physiological impact has yet to be fully determined. Here, we generated C9orf72 DPR knock-in mouse models characterised by expression of 400 codon-optimised polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. This increase in ECM protein levels looked to be a conserved feature of C9ALS/FTD, with a similar signature also present in C9ALS patient iPSC-motor neurons. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human iPSC-neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in C9ALS/FTD patient iPSC motor neurons protected against glutamate-induced cell death. Altogether, our C9orf72 DPR knock-in mice have revealed a neuroprotective and conserved ECM signature in C9ALS/FTD.
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