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GSE34126
Mus musculus
17 Downloadable Samples
Description
Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB, and identify a novel model that can be used to test therapies for this devastating disease.
Publication Title
An animal model of MYC-driven medulloblastoma.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
effect of over-expression LIGHT on T cells for the liver gene expression
Publication Title
Lymphotoxin beta receptor-dependent control of lipid homeostasis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 35 Downloadable Samples
Description
We previously observed that formation of aorta and innominate artery atherosclerotic lesions in the intima of hyperlipidemic apoE-deficient mice but not wild-type mice was accompanied by a marked age-dependent adventitial T cell infiltration. As the mice aged, adventitial T cells formed T/T cell-, T/B cell-, and T/B/dendritic cell aggregates adjacent to atherosclerotic lesions. Some of the adventitial infiltrates formed large clusters of various immune cells including T cells, B cells (centrocytes, follicular mantle cells), dendritic cells, follicular dendritic cells, and plasma cells with preferential formation in the suprarenal portion of the abdominal aorta. These data demonstrated that the immune lineage cell composition of atherosclerotic lesions and adventitia were distinct: The macrophage-foam cell-, T cell-, and SMC-dominated cell composition of atherosclerosis lesions versus the presence of immune cells capable of carrying out antigen-dependent T cell-driven humoral immune responses in the adventitia also indicated that immune reactions carried out in lesions or the adventitia are fundamentaly different. To distinguish between immunity-regulating genes in atherosclerosis lesions versus the adventitia, a combination of microarray profiling and laser capture microdissection was used. Stringent filters revealed 1163 differentially up-regulated probesets in apoE-/- mouse aortae at 78 weeks (w) versus 6 w. A fuzzy c-means cluster algorythm identified 2 clusters that significantly differed in their slope angles between time points: An apparent atherosclerosis cluster consisted of 771 probesets and an apparent adventitia cluster consisted of 392 probesets. Up-regulated genes at 32 w mirrored the influx of monocyte/macrophages into intima lesions whereas genes up-regulated between 32-78 w mirrored adventitial inflammation. To segregate both clusters into separate gene ontology (GO) molecular function groups, we determined statistically significant up-regulation (unpaired Student t-test; p < 0.05) between 6-32 w for the atherosclerosis cluster and between 32-78 w for the adventitia cluster. Among others, GO molecular function terms cytokine activity, cytokine binding, and immunoglobulin binding in the atherosclerosis cluster and cytokine activity, chemokine receptor activity, and antigen binding in the ATLO cluster suggested candidate genes in relation to inflammation triggered by macrophages or adventitia infiltration, respectively. Among other prototype atherosclerosis genes such as Itgax (complement receptor 4), Cd68, Lysz (lysozyme), Vcam1, and Icam1, the atherosclerosis cluster showed markedly overrepresented prototype macrophage/foam cell genes regulating inflammation in cytokine activity (GO: 0005125): Spp1 (osteopontin) and Il6; in cytokine binding (GO: 0019955) Cd74, Il10rb, Ccr2, and Ccr5; and in immunoglobulin binding (GO: 00119865) the proinflammatory galactose-binding lectin Lgals3, as well as genes in scavenger receptor activity and lipid transporter activity. By contrast, the adventitia cluster showed overrepresented genes regulating B cell recruitment, B cell maturation, germinal center formation, and autoimmunity in cytokine activity including Cxcl13, Ccl21, and Ltb, in CXC chemokine receptor activity the secondary lymphoid organ counterreceptor of CXCL13 Blr1 (also known as Cxcr5), Cxcr3, and Cxcr6; and in antigen binding several histocompatibility-2 loci and various markedly expressed immunoglobulin genes. As embryonic lymph node development and tertiary lymphoid organ neogenesis share common features signal intensities of genes specifying the GO molecular function term lymph node development (GO: 0048535) were examined in arrays prepared from wild-type and apoE-/- aortae. These results showed that Id2, Nfkb1, and Ltbr were constitutively expressed at significant levels in aortae of both mouse genotypes whereas other genes including Lta, Ltb, Glycam1, and the two lymphorganogenic genes Cxcl13 and Ccl21 were induced at 78 w in apoE-deficient aortae only. Thus, genes expressed by macrophage-foam cells and genes regulating ATLO neogenesis, embryonic lymph node development, or B cell maturation were constitutively expressed in the arterial wall in both genotypes or emerged in a stepwise fashion at 32 w and 78 w. To verify microarray signal intensity data, separate aortae extracts were examined by quantitative RT-PCR (QRT-PCR) analyses of wild-type and apoE-deficient mice at 32 and 78 w. These data showed that array signal values accurately reflected gene transcripts. Cell lineage analyses of the adventitial infiltrate and kinetic aorta microarray- and QRT-PCR analyses thus provided circumstantial evidence that immune responses in atherosclerosis intima lesions and the adventitia were distinct. To examine this possibility further, we selected areas of the abdominal aorta burdened with advanced lesions and separated lesions and corresponding adventitial infiltrates of 78 w old apoE-deficient mice by laser dissection microscopy. In addition, adventitiae of aorta segments that were not associated with adjacent lesions and adventitiae of wild-type mice were prepared. Consistent with the lack of a major adventitial leukocyte infiltration, wild-type adventitiae showed gene expression levels that were similar to lesion-free adventitiae of apoE-deficient mice indicating that atherosclerotic lesions directly affected adventitial inflammation in a segmental fashion. Stringent filter criteria identified genes that were differentially expressed in adventitiae and atherosclerotic lesions. Statistical analyses of overrepresented genes in GO molecular function or biological process groups were particularly instructive in cytokine activity, cytokine binding, antigen processing and presentation as well as in lymph node development. Thus, adventitiae in aorta segments with associated atherosclerotic lesions in cytokine activity showed overrepresentation of genes known to be associated with tertiary lymphoid organ formation including Cxcl13, Ccl21, and Ltb, whereas atherosclerotic lesions showed overrepresentation of prototype atherosclerosis-associated genes Ssp1 (osteopontin), Bmp4 (bone morphogenic protein 4), and Cxc3cl1 (fractalkine); in cytokine binding adventitiae showed overrepresentation of receptors implicated in B cell immunity and autoimmunity including Brl1 (counterreceptor for CXCL13), Ccr7, Tnfrsf4, and Cxcr3 whereas lesions showed overrepresentation of inflammatory mediator receptors including Tnfrs1b, Tgfbr1, and Il7r; moreover, in antigen processing and presentation, adventitiae showed overrepresentation of several histocompatibility loci; additional adventitial gene expression overrepresentations were observed in lymph node development (Fas, SpiB, Ltb, Flt3) whereas lesions showed expression of prototype macrophage genes including Tlr4, Tgfb1, and Tgfb2. These data provide comprehensive topographical transcriptome information in adventitial tissue adjacent to atherosclerotic lesions versus lesions and are expected to form the basis for future cell lineage expression analyses using single cell detection methodology including ISH.
Publication Title
Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 14 Downloadable Samples
Description
Recurrent somatic mutations in TET2 and in other genes that regulate the epigenetic state have been identified in patients with myeloid malignancies and in other cancers. However, the in vivo effects of Tet2 loss have not been delineated. We report here that Tet2 loss leads to increased stem-cell self-renewal and to progressive stem cell expansion. Consistent with human mutational data, Tet2 loss leads to myeloproliferation in vivo, notable for splenomegaly and monocytic proliferation. In addition, haploinsufficiency for Tet2 confers increased self-renewal and myeloproliferation, suggesting that the monoallelic TET2 mutations found in most TET2-mutant leukemia patients contribute to myeloid transformation. This work demonstrates that absent or reduced Tet2 function leads to enhanced stem cell function in vivo and to myeloid transformation.
Publication Title
Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation.
Sample Metadata Fields
Specimen part
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