Oviductal expression data from wild type and Wt1 heterozygous mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE75924 | GEO | 2015/12/12
SECONDARY ACCESSION(S): PRJNA305723
REPOSITORIES: GEO
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Project description:Comparison of gene expression in wild type and Wt1 (Wilms tumor suppressor gene 1) heterozygous knockout mice. Background: in Wt1+/- mice (MF1 strain) litter sizes are significantly smaller than in wild type animals. In addition, we observe retarded embryonic development of pre-implantation embryos that are still within the oviduct. By gene expression analysis we want to elucidate the molecular basis for these phenomena. 3 wild type and 3 heterozygous RNA samples
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Project description:After fertilization the developing mammalian embryo migrates through the oviduct before it implants in the uterus. In order to prevent tubal pregnancy or failed implantation, development and migration of the embryo has to be tightly coordinated1. The precise molecular basis for the regulation of this maternal-embryonic interaction is largely unknown. Here we show that the Wilms tumor suppressor protein Wt1 is a critical regulator of the interaction between the maternal environment and the early embryo. Our results indicate that subfertility in Wt1ko/+ females is a maternal effect caused by the Wt1-dependent de-regulation of Prss29, encoding a serine protease. Notably, blocking Prss29 activity was sufficient to rescue subfertility in Wt1ko/+ female mice indicating Prss29 as a critical factor in female fertility. Furthermore, we have identified a missense mutation in a patient with idiopathic infertility leading to an amino acid exchange within the zinc finger domain of WT1 and resulting in reduced DNA binding. We demonstrate that Wt1 represses expression of Prss29 and that its de-repression and precocious expression in the oviduct interferes with pre-implantation development. Our study reveals a novel role for Wt1 in early mammalian development and identifies proteases as critical mediators of the maternal-embryonic crosstalk. We believe that our data regarding the importance of a proteostatic environment in the oviduct are also relevant for female fertility in humans. We anticipate that our findings will form the basis for the identification of further causes of idiopathic infertility.
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Project description:Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1. Experiment Overall Design: Identification of WNT/Beta-Catenin or WT1 target genes. 39 individual samples.
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Project description:The Wilms' tumor suppressor gene (WT1) encodes a zinc finger transcription factor that plays important roles during development of several organs including metanephric kidneys. A number of WT1 target genes have been identified, but the detailed mechanisms by which WT1 orchestrates renal development remain elusive. To identify WT1 target genes relevant to development, genome-wide expression profiling was performed using oligonucleotide microarrays representing 39,000 human transcripts Keywords: Wilms' tumor 1 (WT1) gene, -KTS isoform; time course
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Project description:N-degradomic analysis of proteolytic processing in WT1 heterozygous mice, suffering from genetically induced chronic kidney injury, compared to wild type
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Project description:Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1. Keywords: single channel
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Project description:We report the the identification of chrosomal regions bound by the Wilms' tumor suppressor gene WT1 during embryonic mouse kidney development.
2014-06-15 | GSE58179 | GEO
Project description:The Wilms tumor 1 (WT1) gene encodes a zinc finger transcription factor important for normal kidney development. WT1 is a suppressor for Wilms tumor development and an oncogene for diverse malignant tumors. We recently established cell lines from primary Wilms tumors and identified the corresponding WT1 mutations (see GSE18058). To investigate the function of mutant WT1 proteins we performed WT1 knockdown experiments in primary Wilms tumor cell lines with a frameshift/extension (p.V432fsX87 = Wilms3) and a stop mutation (p.P362X = Wilms2) of WT1, followed by genome wide gene expression analysis. A detailed analysis of these gene expression data using MetaCore enabled us to classify the WT1 mutations as gain of function mutations. The mutant WT1Wilms2 and WT1Wilms3 proteins acquired an ability to modulate the expression of a highly significant number of genes from the G2/M phase of the cell cycle, and WT1 knockdown experiments showed that they are required for Wilms tumor cell proliferation. Data from the literature show that p53 negatively regulates the activity of a large number of these genes which are also part of a core proliferation cluster in diverse human cancers. Our data strongly suggest that mutant WT1 proteins facilitate expression of these cell cycle genes by antagonizing transcriptional repression mediated by p53. In light of this it is important to note that mutant WT1 has an ability to physically interact with the tumor suppressor p53. Together the findings show for the first time, that mutant WT1 proteins have a gain of function and act as oncogenes for Wilms tumor development by regulating Wilms tumor cell proliferation.
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Project description:The Wilms tumor 1 (WT1) gene encodes a zinc finger transcription factor important for normal kidney development. WT1 is a suppressor for Wilms tumor development and an oncogene for diverse malignant tumors. We recently established cell lines from primary Wilms tumors and identified the corresponding WT1 mutations (see GSE18058). To investigate the function of mutant WT1 proteins we performed WT1 knockdown experiments in primary Wilms tumor cell lines with a frameshift/extension (p.V432fsX87 = Wilms3) and a stop mutation (p.P362X = Wilms2) of WT1, followed by genome wide gene expression analysis. A detailed analysis of these gene expression data using MetaCore enabled us to classify the WT1 mutations as gain of function mutations. The mutant WT1Wilms2 and WT1Wilms3 proteins acquired an ability to modulate the expression of a highly significant number of genes from the G2/M phase of the cell cycle, and WT1 knockdown experiments showed that they are required for Wilms tumor cell proliferation. Data from the literature show that p53 negatively regulates the activity of a large number of these genes which are also part of a core proliferation cluster in diverse human cancers. Our data strongly suggest that mutant WT1 proteins facilitate expression of these cell cycle genes by antagonizing transcriptional repression mediated by p53. In light of this it is important to note that mutant WT1 has an ability to physically interact with the tumor suppressor p53. Together the findings show for the first time, that mutant WT1 proteins have a gain of function and act as oncogenes for Wilms tumor development by regulating Wilms tumor cell proliferation. siWT1 mediated knockdown in two Wilms tumor cell lines one and two days after transfection versus non-silencing controls
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Project description:We report the the identification of chrosomal regions bound by the Wilms' tumor suppressor gene WT1 during embryonic mouse kidney development. Two indepednent ChIP-Seq experiments on microdissected E18.5 developing mouse kidneys were carried out using either WT1-specific or IgG-antibodies as a negative control.
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