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Mus musculus
7 Downloadable Samples
Description
Enhanced prenatal fatty streak formation in human fetuses has been associated with maternal hypercholesterolemia. However, the possible roles of maternal genetic background and in utero environment on development of atherosclerosis in adult life have not been unraveled. We generated genetically identical heterozygous apoE-deficient mice offspring with a different maternal background to study the intrauterine effect of maternal genotype and associated hypercholesterolemia on the developing vascular system. As read out for increased atherosclerosis development in adult life, a constrictive collar was placed around the carotid artery to induce lesion formation. A significant increase in endothelial cell activation and damage was detected in the carotid arteries of heterozygous apoE-deficient fetuses with apoE-deficient mothers compared with offspring from wild type mothers, but no fatty streak formation was observed. Postnatally, all carotid arteries revealed normal morphology. In adult offspring with maternal apoE-deficiency, the constrictive collar resulted in severe lesion (9/10) development compared with no to only minor lesions (2/10) in offspring of wild type mothers. Microarray analysis showed no effect of maternal apoE-deficiency on gene expression in adult offspring. We conclude that maternal apoE-deficiency not only affects fetal arteries, but also increases the susceptibility for development of collar-induced atherosclerosis in adult life.
Publication Title
Intrauterine exposure to maternal atherosclerotic risk factors increases the susceptibility to atherosclerosis in adult life.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
Description
The human cytomegalovirus (HCMV) encodes the chemokine receptor US28 that exhibits constitutive activity. NIH-3T3 cells stably transfected with US28 present a pro-angiogenic and transformed phenotype both in vitro and in vivo.
Publication Title
The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Description
The spatial organization of DNA in the cell nucleus is an emerging key contributor to genomic function. We have developed 4C technology, or 3C-on-chip, which allows for an unbiased genome-wide search for DNA loci that contact a given locus in the nuclear space. We demonstrate here that active and inactive genes are engaged in many long-range intrachromosomal interactions and can also form interchromosomal contacts. The active b-globin locus in fetal liver contacts mostly transcribed, but not necessarily tissue-specific, loci elsewhere on chromosome 7, while the inactive locus in fetal brain contacts different, transcriptionally silent, loci. A housekeeping gene in a gene dense region on chromosome 8 forms long-range contacts predominantly with other active gene clusters, both in cis and in trans, and many of these intra- and interchromosomal interactions are conserved between the tissues analyzed. Our data demonstrate that chromosomes fold into areas of active chromatin and areas of inactive chromatin and establish 4C technology as a powerful tool to study nuclear architecture.
Publication Title
Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C).
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Bone marrow hematopoietic stem cells (HSCs) are crucial to maintain lifelong production of all blood cells. Although HSCs divide infrequently, it is thought that the entire HSC pool turns over every few weeks, suggesting that HSCs regularly enter and exit cell cycle. Here, we combine flow cytometry with label-retaining assays (BrdU and histone H2B-GFP) to identify a population of dormant mouse HSCs (d-HSCs) within the lin(-)Sca1+cKit+CD150+CD48(-)CD34(-) population. Computational modeling suggests that d-HSCs divide about every 145 days, or five times per lifetime. d-HSCs harbor the vast majority of multilineage long-term self-renewal activity. While they form a silent reservoir of the most potent HSCs during homeostasis, they are efficiently activated to self-renew in response to bone marrow injury or G-CSF stimulation. After re-establishment of homeostasis, activated HSCs return to dormancy, suggesting that HSCs are not stochastically entering the cell cycle but reversibly switch from dormancy to self-renewal under conditions of hematopoietic stress
Publication Title
Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 33 Downloadable Samples
Description
The transcription factor STAT5 plays a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we demonstrate that STAT5 activation cooperates with defects in the pre-BCR signaling components encoded by Blnk, Btk, Prkcb, Nfkb1, and Ikzf1 to initiate B-ALL. STAT5 antagonizes NF-B and IKAROS by opposing regulation of shared target genes. STAT5 binding was enriched at super-enhancers, which were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4, and IKAROS. Patients with high ratios of active STAT5 to NF-B or IKAROS have more aggressive disease. Our studies illustrate that an imbalance of two opposing transcriptional programs drive B-ALL, and suggest that restoring the balance of these pathways may inhibit B-ALL.
Publication Title
Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 2 Downloadable Samples
Description
IKK kinase is essential for the B cell maturation and secondary lymphoid organ development. In the current study, we evaluated the role of IKK in the marginal zone and follicular B lymphocyte development by genetically deleting IKK from the B cell lineage using CD19-Cre mice. The loss of IKK did not affect the normal development of early B cell progenitors. However, a significant decline was observed in the percentage of immature B lymphocytes, mature marginal zone and follicular B cells along with a severe disruption of splenic marginal and follicular B cell zones. A gene expression analysis performed on the RNA extracted from the newly formed B cells (B220+IgMhi) revealed that IKK deficiency produces significant changes in the expression of genes involved in MZ and FO B lymphocyte survival, homing and migration. And several among those genes identified belong to G protein family. Specifically, we validated the upregulated expression of regulator of G protein signaling 13 (RGS13), which is a GTPase activating protein (GAP) that negatively regulates G protein signaling and impede B cell migration. Likewise, promigratory B lymphocyte receptor, the sphingosine-1-phosphate receptor 3 (SIPR3) that couple to Gi showed significantly reduced expression. In addition, an in silico analysis of gene product interactions revealed NF-B signaling pathways to be a major gene regulating networks perturbed with IKK deletion. Taken together, this study reveals IKKNF-B and G protein signaling axis to be central for the MZ and FO B cells survival, maintenance, homing and migration.
Publication Title
IKKα deficiency disrupts the development of marginal zone and follicular B cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
Description
Sphingosine 1-phosphate (S1P) is a bioactive lipid whose levels are tightly regulated by its synthesis and degradation. Intracellularly, S1P is dephosphoryled by the actions of two S1P-specific phosphatases, sphingosine 1-phosphate phosphatase 1 and 2. To identify the physiologic functions of S1P phosphatase 1, we have studied mice with its gene, Sgpp1, deleted. Sgpp1-/- mice appeared normal at birth but during the first week of life, they exhibited stunted growth, suffered desquamation, and most died before weaning. Interestingly, the epidermal permeability barrier developed normally during embryogenesis. Sgpp1 -/- pups and surviving adults exhibited epidermal hyperplasia and abnormal expression of keratinocyte differentiation markers. Keratinocytes isolated from Sgpp1 -/- skin had increased intracellular S1P levels, and expressed a gene expression profile that indicated enhanced differentiation. The results reveal S1P metabolism as a regulator of keratinocyte differentiation and epidermal homeostasis.
Publication Title
Sphingosine-1-phosphate phosphatase 1 regulates keratinocyte differentiation and epidermal homeostasis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 3 Downloadable Samples
Description
We generated Ikk-KA/KA knock-in mice (KA/KA), in which an ATP binding site of Ikk Lys 44 was replaced by alanine. The knock-in mice develop severe skin lesions and begin to die after 6 to 10 months. We also found lung SCCs in some of the mice. To study lung SCC development, we stabilize the skin condition by crossing KA/KA with Lori.Ikk transgenic mice to generate KA/KA-Lori.Ikk mice, which 100% spontaneously developed lethal lung SCC at 4 to 6 months of age.
Publication Title
The pivotal role of IKKα in the development of spontaneous lung squamous cell carcinomas.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Deletion of the gene encoding Foxa2, a winged helix transcription factor selectively expressed in respiratory epithelial cells, caused spontaneous pulmonary eosinophilic inflammation and goblet cell metaplasia. Loss of Foxa2 induced the recruitment and activation of myeloid dendritic cells (mDCs) and Th2 cells in the lung, and was associated with the increased production of T helper 2 (Th2) cytokines and chemokines. mRNA microarray analysis demonstrated that deletion of Foxa2 induced the expression of a number of mRNAs regulating pulmonary dendritic cell activation, Th2 mediated inflammation, and goblet cell differentiation. The spontaneous pulmonary inflammation and goblet cell metaplasia caused by loss of Foxa2 was inhibited by treatment of newborn Foxa2/ mice with monoclonal IL-4Ralpha antibody. Expression of Foxa2 in non-ciliated secretory cells (Clara cells) in vivo inhibited goblet cell differentiation induced by pulmonary allergen exposure. The respiratory epithelium plays a central role in the regulation of Th2-mediated inflammation and innate immunity in the developing lung in a process regulated by Foxa2.
Publication Title
Foxa2 programs Th2 cell-mediated innate immunity in the developing lung.
Sample Metadata Fields
Specimen part
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GSE60615- Mus musculus
- 24 Downloadable Samples
Description
Foxp3+ regulatory T (Treg) cells prevent inflammatory disease but the mechanistic basis of suppression is not understood completely . Gene silencing by RNA interference can act in a cell-autonomous and non-cell-autonomous manner, providing mechanisms of inter-cellular regulation. Here, we demonstrate that non-cell-autonomous gene silencing, mediated by miRNA-containing exosomes, is a mechanism employed by Treg cells to suppress T cell-mediated disease. Treg cells transferred microRNAs (miRNA) to various immune cells, including T helper 1 (Th1) cells, suppressing Th1 cell proliferation and cytokine secretion. Use of Dicer-deficient or Rab27a and Rab27b double-deficient Treg cells to disrupt miRNA-biogenesis or the exosomal pathway, respectively, established a requirement for miRNAs and exosomes for Treg cell-mediated suppression. Transcriptional analysis and miRNA inhibitor studies showed that exosome-mediated transfer of Let-7d from Treg cell to Th1 cells contributed to suppression and prevention of systemic disease. These studies reveal a mechanism of Treg cell-mediated suppression mediated by miRNA-containing exosomes.
Publication Title
MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells.
Sample Metadata Fields
Specimen part
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