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GSE35181
Mus musculus
6 Downloadable Samples
Description
Biased GPCR agonists are orthosteric ligands that possess pathway-selective efficacy, activating or inhibiting only a subset of the signaling repertoire of their cognate receptors. In vitro, D-Trp12,Tyr34-bPTH(7-34) (PTH-{beta}arr), a biased agonist for the type 1 parathyroid hormone receptor, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, both PTH-{beta}arr and the conventional agonist PTH(1-34) stimulate anabolic bone formation. To understand how two PTH1R ligands with markedly different in vitro efficacy could elicit similar in vivo responses, we analyzed transcriptional profiles from calvarial bone of mice treated for 8 weeks with vehicle, PTH-{beta}arr or PTH(1-34). Treatment of wild type mice with PTH-{beta}arr primarily affected pathways that promote expansion of the osteoblast pool, notably cell cycle regulation, cell survival and migration. These responses were absent in beta-arrestin2 null mice, identifying them as downstream targets of beta-arrestin2-mediated signaling. In contrast, PTH(1-34) primarily affected pathways classically associated with enhanced bone formation, including collagen synthesis and matrix mineralization. PTH(1-34) actions were less dependent on beta-arrestin2, as might be expected of a ligand capable of G protein activation. These results illustrate the uniqueness of biased agonism in vivo and demonstrate that functional selectivity can be exploited to change the quality of GPCR efficacy.
Publication Title
β-arrestin-selective G protein-coupled receptor agonists engender unique biological efficacy in vivo.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 10 Downloadable Samples
Description
This study compared gene expression in murine bcr-abl positive acute lymphoblastic leukemia cells in vivo in allogeneic BMT recipients compared to syngneneic BMT recipients.
Publication Title
Differential gene expression in acute lymphoblastic leukemia cells surviving allogeneic transplant.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
Description
Phosphorylation and subsequent nuclear translocation of SMAD proteins determine the cellular response to activin. Here we identify a novel means by which activin signalling is regulated to enable developmental stage-specific SMAD gene transcription. In response to activin A, immature proliferating mouse Sertoli cells exhibit nuclear accumulation of SMAD3, but not SMAD2, although both proteins are phosphorylated. In post-mitotic differentiating cells, both SMAD2 and SMAD3 accumulate in the nucleus. Furthermore, immature Sertoli cells are sensitive to activin dosage; at higher concentrations maximal SMAD3 nuclear accumulation is observed, accompanied by a small, but significant, increase in nuclear SMAD2. Microarray analysis confirmed that differential SMAD utilization correlated with altered transcriptional outcomes and identified new activin target genes, Gja1 and Serpina5, which are known to be required for Sertoli cell development and male fertility. In immature Sertoli cells, genetic or transient knockdown of SMAD3 enhanced SMAD2 nuclear accumulation in response to activin, with increased Serpina5 mRNA levels associated with nuclear localized SMAD2. In transgenic mice with altered activin bioactivity that display male fertility phenotypes, testicular Gja1 and Serpina5 mRNA levels reflected altered in vivo activin levels. We conclude that regulated nuclear accumulation of phosphorylated SMAD2 is a novel determinant of developmentally regulated activin signalling.
Publication Title
Developmentally regulated SMAD2 and SMAD3 utilization directs activin signaling outcomes.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 10 Downloadable Samples
Description
From preliminary experiments, HSP70 deficient MEF cells display moderate thermotolerance to a severe heatshock of 45.5 degrees after a mild preshock at 43 degrees, even in the absence of hsp70 protein. We would like to determine which genes in these cells are being activated to account for this thermotolerance.
Publication Title
Microarray analysis of cellular thermotolerance.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Description
We have identified a population of adipocytes in fat tissue that arise from bone marrow-derived progenitor cells.
Publication Title
De novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age, adipose depot, and gender specific.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Pofut1 is an essential gene that glycosylates proteins containing EGF-like repeats, including Notch Receptors (NotchRs). Work in mice and in Drosophila has shown that O-fucosylation by Pofut1 is required for NotchR ligands to bind to and activate NotchRs. As such, Pofut1 deletion in skeletal myofibers allows for an analysis of potential functions and molecular changes of Pofut1 in skeletal muscle that derive from its expression in skeletal myofibers. In this study we compared gene expression profiles between quadriceps muscles in mice where Protein O-fucosyltransferase 1 (Pofut1) was deleted specifically in skeletal myofibers via use of a human skeletal alpha actin Cre transgene (Scre) and a loxP flanked Pofut1 gene (SCreFF) and mice which bore the only the Scre transgene but did not have floxed Pofut1 alleles (SCre++).
Publication Title
Deletion of <i>Pofut1</i> in Mouse Skeletal Myofibers Induces Muscle Aging-Related Phenotypes in <i>cis</i> and in <i>trans</i>.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
Description
Background and Aims: Although the zinc finger transcription factor GATA4 has been implicated in regulating jejunal gene expression, the contribution of GATA4 in controlling jejunal physiology has not been addressed. Methods: We generated mice in which the Gata4 gene was specifically deleted in the small intestinal epithelium. Measurements of plasma cholesterol and phospholipids, intestinal absorption of dietary fat and cholesterol, and gene expression were performed on these animals. Results: Mice lacking GATA4 in the intestine displayed a dramatic block in their ability to absorb cholesterol and dietary fat. Comparison of the global gene expression profiles of control jejunum, control ileum, and GATA4 null jejunum by gene array analysis demonstrated that GATA4 null jejunum lost expression of 53% of the jejunal-specific gene set and gained expression of 47% of the set of genes unique to the ileum. These alterations in gene expression included a decrease in mRNAs encoding lipid and cholesterol transporters as well as an increase in mRNAs encoding proteins involved in bile acid absorption. Conclusion: Our data demonstrate that GATA4 is essential for jejunal function including fat and cholesterol absorption and confirm that GATA4 plays a pivotal role in determining jejunal versus ileal identity.
Publication Title
GATA4 is essential for jejunal function in mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Nanoemulsion mucosal adjuvant uniquely activates cytokine production by nasal ciliated epithelium and induces dendritic cell trafficking.
Sample Metadata Fields
Sex, Age, Specimen part, Time
View Samples- Mus musculus
- 4 Downloadable Samples
Description
Ubiquitination is a post-translational mechanism of control of diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes including Notch1, c-Myc and cyclin E. We have generated conditional Fbw7 knock-out animals and inactivated the gene in hematopoietic stem cells (HSC) and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects the HSC compartment in a cell-autonomous manner. Fbw7-/- HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7-/- HSC are unable to colonize the thymus leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E are stabilized in the bone marrow of Fbw7 deficient mice. Genome-wide transcriptome studies of Fbw7-/- HSC and hematopoietic progenitors indicate that Fbw7 controls, through the regulation of HSC cell cycle entry, the global transcriptional signature that is associated with the quiescent, self-renewing HSC phenotype.
Publication Title
Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
Description
Antigen uptake, processing and presentation by dendritic cells are regulated by complex intra- and inter-cellular signalling events. Typical vaccine adjuvants lead to the transcription of pro-inflammatory cytokines and chemokines which relate to immune induction.
Publication Title
Nanoemulsion mucosal adjuvant uniquely activates cytokine production by nasal ciliated epithelium and induces dendritic cell trafficking.
Sample Metadata Fields
Sex, Age, Specimen part, Time
View Samples