Affymetrix array gene expression analysis using RNA isolated from Purkinje cells and ventricular myocytes from the Cntn2-EGFP/ a-MHC-Cre/ floxed-tdTomato compound transgenic dual fluorescence reporter mouse
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Sex, Specimen part
View SamplesPf1, also known as Phf12 (plant homeodomain (PHD) zinc finger protein 12) is a member of the PHD zinc finger family. Pf1 was first identified in a yeast-two hybrid screen for proteins interacting with the paired amphipathic helix (PAH) 2 domain of mSin3A, and shown to function as a transcriptional repressor . We generated Pf1 knockout mice to define the physiological role of Pf1.
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View SamplesWe isolated fetal murine urogenital sinus epithelium and urogenital sinus mesenchyme and determined their global gene expression profiles to define their differentially expressed regulators. To distinguish gene expression patterns that are shared by other developing epithelial/mesenchymal compartments in the embryo from those that pertain to the prostate stem cell niche, we also determine the global gene expression of epidermis and dermis of the same embryos. We identified a distinctive core of transcripts that were differentially regulated in the prostate stem cell niche. Our analysis indicates that several of the key transcriptional components that are likely to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal (e.g., E2f and Ap2), lipid metabolism (e.g., Serbp1) and cell migration (e.g., Areb6 and Rreb1). Several of the promoter binding motifs that are enriched in the profiles are shared between the prostate epithelial/mesenchymal compartments and their epidermis/dermis counterparts, indicating their likely relevance in epithelial/mesenchymal signaling in primitive cellular compartments. We also focused on defining ligand-receptor interactions that may be relevant in controlling signals in the stem cell niche and identified the Wnt/beta-catenin, ephrin, Notch, sonic hedgehog, FGF, TGF-beta and bone morphogenic signaling pathways as being of likely relevance in the prostate stem cell niches. Members of the integrins family including those that bind extracellular matrix proteins such as laminin and activate latent TGF-beta are also expressed in the prostate niche.development.
Molecular signatures of the primitive prostate stem cell niche reveal novel mesenchymal-epithelial signaling pathways.
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View SamplesThe global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer. A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem cells include expression profiles of Wnt, Shh and other pathways identified in stem cells of other organs, signatures of the aryl-hydrocarbon receptor, and up-regulation of components of the aldehyde dehydrogenase/retinoic acid receptor axis. There is also a significant lipid metabolism signature, marked by overexpression of lipid metabolizing enzymes and the presence of the binding motif for Srebp1. The fetal stem cell population, characterized by more rapid proliferation and self-renewal, expresses regulators of the cell cycle, such as E2f, Nfy, Tead2 and Ap2, at elevated levels, while adult stem cells show a signature in which TGF- has a prominent role. Finally, comparison of the signatures of primitive prostate cells with previously described profiles of human prostate tumors identified stem cell molecules and pathways with deregulated expression in prostate tumors including chromatin modifiers and the oncogene, Erg. Our data indicate that adult prostate stem or progenitor cells may acquire characteristics of self-renewing primitive fetal prostate cells during oncogenesis and suggest that aberrant activation of components of prostate stem cell pathways may contribute to the development of prostate tumors.
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Sex, Specimen part
View SamplesActivation of oncogenic ras pathway accounts for up to 90% low-grade superficial urothelial carcinomas of bladder, and p53 deficiency is very common in high-grade muscle invasive carcinomas. These two pathways in bladder urothelial tumorigenesis used to be considered divergent and their potential collaboration has not been illustrated.
Oncogenic HRAS Activates Epithelial-to-Mesenchymal Transition and Confers Stemness to p53-Deficient Urothelial Cells to Drive Muscle Invasion of Basal Subtype Carcinomas.
Age, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Novel Foxo1-dependent transcriptional programs control T(reg) cell function.
Specimen part
View SamplesMemory T cells provide immunity against pathogen reinvasion, but mechanisms of their long-term maintenance is unclear. Here we show that mice with the deletion of the transcription factor Foxo1 in activated CD8+ T cells had defective secondary but not primary responses to Listeria monocytogenes infection. Compared to short-lived effector T cells, memory precursor effector T cells expressed higher amounts of Foxo1 that promoted their generation and maintenance. Gene expression profiling and chromatin immunoprecipitation sequencing experiments revealed the chemokine receptor CCR7 and the transcription factor TCF1 as novel Foxo1-bound target genes with critical functions in memory T cell trafficking and transcriptional regulation. These findings demonstrate that Foxo1 is selectively incorporated into the genetic program that regulates memory but not effector CD8+ T cell responses to infection.
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Specimen part
View SamplesRegulatory T (Treg) cells characterized by expression of the transcription factor forkhead box P3 (Foxp3) maintain immune homeostasis by suppressing self-destructive immune responses1-4. Foxp3 operates as a late acting differentiation factor controlling Treg cell homeostasis and function5, whereas the early Treg cell lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors6-10. However, whether Foxo proteins act beyond the Treg cell commitment stage to control Treg cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of Treg cell function. Treg cells express high amounts of Foxo1, and display reduced T-cell receptor-induced Akt activation, Foxo1 phosphorylation, and Foxo1 nuclear exclusion. Mice with Treg cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to Foxp3-deficient mice, but without the loss of Treg cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the proinflammatory cytokine Ifng, that do not appear to be directly regulated by Foxp3. These findings demonstrate that the evolutionarily ancient Akt-Foxo1 signaling module controls a novel genetic program indispensable for Treg cell function.
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Specimen part
View SamplesGerm free (GF) and conventionalized (CONV-D) wild-type C57Bl/6 male mice in the CARB-fed, 24h fasted, and 30d trained states; plus GF and CONV-D CARB-fed Ppara-/- mice. CARB-fed indicates a standard polysaccharide-rich mouse chow diet.
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Sex, Specimen part
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