Expression data from acd, p53 and double mutant mouse embryos
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE95806 | GEO | 2018/09/07
REPOSITORIES: GEO
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Project description:DNA from tumors of 10 male mice were competitively hybridized with DNA from liver samples from the same mouse on NimbleGen CGH arrays to assess copy number changes in the tumors. Four of the mice were wildtype for Acd (ortholog of human TPP1), 2 of which were p53-/- and 2 of which were p53-/+. The other 6 mice were homozygous for the mutant acd allele of Acd. 3 of these mice were p53-/- and the other 3 were p53-/+. Mice were crosses from double heterozygote parental mice. These parental mice were crosses of heterozygous Acd mutant mice (in a mixed DW/JxCAST/Ei background) with heterozygous null p53 mice (C57BL6/J; Trp53-tm1Tyj).
2009-04-07 | E-TABM-680 | biostudies-arrayexpress
Project description:Expression data from acd, p53 and double mutant mouse embryos
| PRJNA378483 | ENA
Project description:We tested whether loss of p53 function leads to insulin-like growth factor 2 (IGF2) pathway dependency in vivo in genetically defined mouse models. Unexpectedly we found lethality, due to post-natal lung haemorrhage, occurred in Igf2 paternal null allele female mice (Igf2-p) but only if derived from double heterozygote fathers (Igf2-p, p53+/-). Consequently we investigated the effects of paternal genotype (wild-type, Igf2-p and Igf2-p, p53+/-) on gene expression. Microarray gene expression profiling of whole mouse embryos (embryonic day 9.5) revealed that lethality was associated with a specific gene signature. Since double heterozygote female offspring (Igf2-p, p53+/-) of Igf2-p, p53+/- fathers did not have the lethality phenotype we identified gene expression changes associated with this 'rescue'. Supplementary information available when browsing all available files.
2012-06-01 | E-MTAB-1001 | biostudies-arrayexpress
Project description:Caspase-8 is a protease with both pro-death and pro-survival functions: it is required for apoptosis induced by death receptors such as TNFR1 (tumour necrosis factor receptor 1), and it has a critical role in suppressing necroptosis mediated by the kinase RIPK3 (receptor interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase-like). Mice lacking caspase-8 display MLKL-dependent embryonic lethality, as do mice expressing catalytically inactive caspase-8 mutant C362A. However, Casp8C362A/C362A Mlkl-/- mice die in the perinatal period, whereas Casp8-/- Mlkl-/- mice are viable, indicating that inactive caspase-8 also has a pro-death scaffolding function. Here we show that caspase-8 C362A triggers ASC speck formation and caspase-1-dependent pyroptosis in MLKL-deficient intestinal epithelial cells (IECs) around embryonic day 18. Pyroptosis contributed to the perinatal lethal phenotype because a number of Casp8 C362A/C362A Mlkl-/- Casp1-/- mice survived beyond weaning. Transfection studies suggested inactive caspase-8 adopts a distinct conformation to wild-type caspase-8, enabling it to engage the caspase-1 adaptor ASC. Wild-type caspase-8 was found in the Triton X-100 soluble fraction, whereas wild-type caspase-8 inhibited with the pan-caspase inhibitor emricasan, or inactive caspase-8 mutant C362A, were detected in the insoluble fraction. Moreover, inhibited or inactive caspase-8 shifted ASC into the insoluble fraction. Perinatal lethality was recapitulated when expression of caspase-8 C362A was restricted to IECs, but intriguingly, only in the absence of MLKL. Hence, unanticipated plasticity in death pathways is revealed such that IECs can undergo caspase-1-dependent death when caspase-8-dependent apoptosis and MLKL-dependent necroptosis are inhibited.
2019-09-20 | GSE132133 | GEO
Project description:Purpose: Citron kinase (CitK) knockout mice show a severe form of primary microcephaly, associated with ataxia and lethal epilepsy. This phenotype is caused by massive apoptosis occuring during embryonic and post-natal brain development, associated with cytokinesis failure. Cerebellum is the tissue showing highest sensitivity to CitK loss. The clinical phenotype of CitK knockout mice is significantly resued by P53 inactivation. In addition, CitK/P53 double knockout brains have almost normal levels of apoptosis, but display high percentage of binucleated and multinucleated cells. The aim of this study was to analyze the gene expression changes produced in developing neural tissue by CitK loss and to determine which alterations are P53-dependent. expression changes Methods: We analyzed by RNA sequencing total RNA extracted from P4 cerebellum of mice characterized by the following genotypes: 1. CitK +/-, P53 +/- (CTRL); 2. CitK -/-, P53 +/- (CitK-KO); 3. CitK +/-, P53 -/- (P53-KO); 4. CitK -/-, P53 -/- (D-KO). Biological triplicates were analyzed per every genotype. Conclusions: The loss of CitK leads to a strong reduction of the expression of pro-neural genes and induces a P53-related pro-apoptotic gene sets. The analysis of D-KO mice reveals that most of these changes are P53-dependent, but many genes implicated in growth arrest are induced through P53-independent mechanisms.
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Project description:Mutations in the Notch1 receptor and delta-like 3 (Dll3) ligand cause global disruptions in axial segmental patterning. Genetic interactions between members of the notch pathway have previously been shown to cause patterning defects not observed in single gene disruptions. We examined Dll3-Notch1 compound mouse mutants to screen for potential gene interactions. While mice heterozygous at either locus appeared normal, 30% of Dll3-Notch1 double heterozygous animals exhibited localized, stochastic segmental anomalies similar to human congenital vertebral defects. Unexpectedly, double heterozygous mice also displayed statistically significant decreases in mandibular height and elongated maxillary hard palate. Examination of somite-stage embryos and perinatal anatomy and histology did not reveal any organ defects, so we used microarray-based analysis of Dll3 and Notch1 mutant embryos to identify gene targets that may be involved in notch-regulated segmental or craniofacial development. Therefore, Dll3-Notch1 double heterozygous mice model human congenital scoliosis and craniofacial disorders. Keywords: genotype comparison
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Project description:MICU1 is a Ca2+-binding protein that regulates the mitochondrial Ca2+ uniporter channel (mtCU ) and mitochondrial Ca2+ (mCa2+) uptake. MICU1 knockout mice display perinatal lethality and disorganized mitochondrial architecture. These phenotypes are distinct from other mtCU loss-of-function models and thus are not explained by changes in mCa2+ content. Utilizing multiple proteomic approaches, we found that MICU1 localized to mitochondrial complexes lacking MCU, suggesting that MICU1 has cellular functions independent of mCa2+ uptake. The overall aim of the current project is to identify the global and mtCU independent MICU1 interactome to characterize the MCU independent functions of the MICU1.
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Project description:Ssb1(NABP2/OBFC2A) and Ssb2 (NABP1/OBFC2B) are two closely related proteins that show functional redundancies supported by their existence in two separate subcomplexes with identical proteins. Ssb1 knockout causes perinatal lethality in mice, Ssb2 knockout does not associate with any observable phenotypes, however, double knockout of both Ssb1/2 causes embryonically lethality. Notably, conditional loss of both in adult mice leads to acute lethality due to bone marrow and gut failure. Here, we further demonstrate that the overlapping essential function of both Ssb1/2 is through their prime binding partner IntS3, a member of the multiprotein complex called the Integrator. The Integrator complex interacts with the largest subunit of RNA Polymerase II and is required for processing and termination of small nuclear RNAs (snRNAs). Here, we provide a firsthand evidence that the stability of the Integrator complex is compromised in mouse-embryonic fibroblasts (MEFs) with compound loss of both Ssbs. We further demonstrate that these MEFs show overexpression of unprocessed snRNAs which forces the cells to express alternative spliced variants of genes that are required for transcription and cell cycle regulation. This phenotype closely phenocopies loss of core integrator subunit, IntS11 as well as splicing components B and C. Interestingly, the phenotype gets partially restored by overexpression of wildtype Ssb1 but not by the Ssb-mutant defective in binding integrator subunit, IntS3, demonstrating the essential roles of Ssb1/2 in the maintenance of the Integrator complex and thereby, genomic stability.
2022-03-11 | GSE155240 | GEO
Project description:Palb2 interacts with BRCA1 and BRCA2 in supercomplexes involved in DNA repair via homologous recombination. Heterozygous germline mutations in PALB2 confer a moderate risk of breast cancer while biallelic PALB2 mutations are linked to a severe form of Fanconi anaemia characterized by early childhood solid tumours and severe chromosomal instability. In contrast to BRCA1- or BRCA2-associated cancers, breast tumours in heterozygous PALB2 mutation carriers do not show loss of the wild type allele, suggesting PALB2 might be haploinsufficient for tumour suppression. To study the role of PALB2 in development and tumourigenesis, we have generated Palb2GT mouse mutants using a gene trap approach. Whereas Palb2GT/GT homozygous mutant embryos died at mid-gestation due to massive apoptosis, Palb2GT/+ heterozygous mice were viable and did not show any obvious abnormalities. Deletion of p53 alleviated the phenotype of Palb2GT/GT embryos, but did not rescue embryonic lethality. In addition, loss of p53 did not significantly collaborate with Palb2 heterozygosity in tumourigenesis in heterozygous or homozygous p53 knockout mice. Tumours arising in Palb2GT/+;p53+/– or Palb2GT/+;p53–/– compound mutant mice retained the wild type Palb2 allele and did not display increased genomic instability. Comparison of 15 Palb2GT/+;p53-/- and 11 Palb2+/+;p53-/- lymphomas. Spleen/liver DNA of the same animal was used as reference material.
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Project description:The Deciphering the Mechanisms of Developmental Disorders (DMDD) programme analyses the morphological and molecular phenotypes of embryonic and perinatal lethal mouse mutant lines. Here we show that single whole embryo RNA-seq of 73 mouse mutant lines (>1000 transcriptomes) uncovers transcriptional events underlying embryonic lethality and associates previously uncharacterised genes with specific pathways and tissues. Further, we separate embryonic delay signatures from line-specific transcriptional changes by developing a baseline mRNA expression catalogue of wild-type mice during somitogenesis. Collectively, this work provides a rich resource to further our understanding of early embryonic developmental disorders.
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