Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of pancreatic islets in Tcf1 knock out mice and wild type mice to understand the effects of Tcf1 knockout on gene expression.

ABSTRACT: Expression profiling of pancreatic islets in Tcf1 knock out mice. Experiment Overall Design: two biological replicates per condition; two conditions are WT and Tcf1 KO mice; platforms are Affy MG-U74A and B array

ORGANISM(S): Mus musculus

SUBMITTER: Markus Stoffel

PROVIDER: E-GEOD-3544 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Tmem27: a cleaved and shed plasma membrane protein that stimulates pancreatic beta cell proliferation.

Akpinar Pinar P Kuwajima Satoru S Krützfeldt Jan J Stoffel Markus M

Cell metabolism 20051201 6

The signals and molecular mechanisms that regulate the replication of terminally differentiated beta cells are unknown. Here, we report the identification and characterization of transmembrane protein 27 (Tmem27, collectrin) in pancreatic beta cells. Expression of Tmem27 is reduced in Tcf1(-/-) mice and is increased in islets of mouse models with hypertrophy of the endocrine pancreas. Tmem27 forms dimers and its extracellular domain is glycosylated, cleaved and shed from the plasma membrane of b ...[more]

PMID: 16330324

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Project description:The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1-/- mice have previously been characterized and show developmental blocks at the CD4-CD8- double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1-/- mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1-/- mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell‚Äìspecific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus. Using the Tcf1-/- DeltaVII/DeltaVII knockout mouse (Verbeek et al. Nature 1995), thymocytes of 17 mice (5 control Tcf+/-, 4 Tcf-/- and 8 Tcf-/- with thymic lymphoma) were homogenized for RNA isolation using Qiagen RNeasy minicolumns. The quantity and quality of total RNA was determined using spectrophotometry (Nanodrop) and an Agilent Bioanalyzer. One ¬µg of RNA was used to generate cRNA using Affymetrix One cycle cDNA synthesis kit (Affymetrix, Santa Clara, CA, USA), after which the samples were biotinylated using an Affymetrix IVT labeling kit (Affymetrix). The samples were hybridized overnight at 42¬?C to GeneChip mouse genome 430 2.0 Arrays (Affymetrix). Washing and staining steps were performed on a Fluidics station 450, and the Genechips were scanned using a GeneChip scanner 3000 (Affymetrix) at the Department of Immunology, Erasmus Medical Center. Raw data were normalized and summarized using Robust Multichip Average (RMA) method. The experiment consists of 5 control Tcf+/- thymi, 4 Tcf-/- thymi and 8 Tcf-/- thymus samples with thymic lymphoma.

Project description:The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1−/− mice have previously been characterized and show developmental blocks at the CD4−CD8− double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1−/− mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1−/− mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell–specific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus. Using the Tcf1−/− ΔVII/ΔVII knockout mouse (Verbeek et al. Nature 1995), thymocytes of 17 mice (5 control Tcf+/-, 4 Tcf-/- and 8 Tcf-/- with thymic lymphoma) were homogenized for RNA isolation using Qiagen RNeasy minicolumns. The quantity and quality of total RNA was determined using spectrophotometry (Nanodrop) and an Agilent Bioanalyzer. One µg of RNA was used to generate cRNA using Affymetrix One cycle cDNA synthesis kit (Affymetrix, Santa Clara, CA, USA), after which the samples were biotinylated using an Affymetrix IVT labeling kit (Affymetrix). The samples were hybridized overnight at 42°C to GeneChip mouse genome 430 2.0 Arrays (Affymetrix). Washing and staining steps were performed on a Fluidics station 450, and the Genechips were scanned using a GeneChip scanner 3000 (Affymetrix) at the Department of Immunology, Erasmus Medical Center. Raw data were normalized and summarized using Robust Multichip Average (RMA) method.

Dataset Information

Transcription profiling of pancreatic islets in Tcf1 knock out mice and wild type mice to understand the effects of Tcf1 knockout on gene expression.

Publications

Tmem27: a cleaved and shed plasma membrane protein that stimulates pancreatic beta cell proliferation.

Similar Datasets

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