Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA311906 | ENA |
REPOSITORIES: ENA
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Project description:Receptor tyrosine kinases MET and EGFR are critically involved in initiation of liver regeneration. Other cytokines and signaling molecules also help in the early part of the process. Regeneration employs effective redundancy schemes to compensate for missing signals. Elimination of any single signaling pathway only delays but does not abolish the process. Our present study, however, shows that combined systemic elimination of MET and EGFR signaling abolishes liver regeneration, prevents restoration of liver mass and leads to liver decompensation. Our results demonstrate that liver function is dependent on synchronous availability of signaling from these two pathways. The study shows that MET and EGFR separately control many non-overlapping signaling endpoints, allowing for compensation when only one of the signals is blocked. The combined elimination of the signals however was not tolerated. The results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to regeneration arrest and liver decompensation. We used microarrays to detail the global programme of gene expression in METKO-canertinib mouse liver following a partial hepatectomy
2016-10-27 | GSE77867 | GEO
Project description:MET and EGFR receptor tyrosine kinases are crucial for liver regeneration and normal hepatocyte function. Recently we demonstrated that in mice, combined inhibition of these two signaling pathways abolished liver regeneration following hepatectomy, with subsequent hepatic failure and death at 15-18 days post-resection. Morbidity was associated with distinct and specific alterations in important downstream signaling pathways that led to a decrease in hepatocyte volume, reduced proliferation, and shutdown of many essential hepatocyte functions such as fatty acid synthesis, urea cycle, and mitochondrial functions. In the present study we explore the role of MET and EGFR signaling in resting mouse livers that are not subjected to hepatectomy. Mice with combined disruption of MET and EGFR signaling (Delta MET + EGFRi) were noticeably sick by 10 day and died at 12-14 days. Delta MET + EGFRi mice showed decreased liver to body weight ratios, increased apoptosis in non-parenchymal cells, impaired liver metabolic functions, and activation of distinct, downstream signaling pathways related to inflammation, cell death, and survival. Conclusion: The present study demonstrates that in addition to controlling the regenerative response, MET and EGFR synergistically control baseline liver homeostasis in normal mice in such a way that their combined disruption leads to liver failure and death. We used microarrays to detail the global programme of gene expression in Delta MET + EGFRi mice liver vs control mice liver
2018-07-09 | GSE116307 | GEO
Project description:TCPOBOP (1,4-Bis [2-(3,5-Dichloropyridyloxy)] benzene) is a constitutive androstane receptor (CAR) agonist that induces robust hepatocyte proliferation and hepatomegaly without any liver injury or tissue loss. TCPOBOP-induced direct hyperplasia has been considered to be CAR-dependent with no evidence of involvement of cytokines or growth factor signaling. Receptor tyrosine kinases (RTKs), MET and EGFR, are known to play a critical role in liver regeneration after partial hepatectomy, but their role in TCPOBOP-induced direct hyperplasia, not yet explored, is investigated in the current study. Disruption of the RTK-mediated signaling was achieved utilizing MET KO mice along with Canertinib treatment for EGFR inhibition. Combined elimination of MET and EGFR signaling [MET KO + EGFRi], but not individual disruption, dramatically reduced TCPOBOP-induced hepatomegaly and hepatocyte proliferation. TCPOBOP-driven CAR activation was not altered in [MET KO + EGFRi] mice, as measured by nuclear CAR translocation and analysis of typical CAR target genes. However, TCPOBOP induced cell cycle activation was impaired in [MET KO + EGFRi] mice due to defective induction of cyclins, which regulate cell cycle initiation and progression. TCPOBOP-driven induction of FOXM1, a key transcriptional regulator of cell cycle progression during TCPOBOP-mediated hepatocyte proliferation, was greatly attenuated in [MET KO + EGFRi] mice. Interestingly, TCPOBOP treatment caused transient decline in HNF4α expression concomitant to proliferative response; this was not seen in [MET KO + EGFRi] mice. Transcriptomic profiling revealed vast majority (~40%) of TCPOBOP-dependent genes mainly related to proliferative response, but not to drug metabolism, were differentially expressed in [MET KO + EGFRi] mice. Conclusion: Taken together, combined disruption of EGFR and MET signaling lead to dramatic impairment of TCPOBOP-induced proliferative response without altering CAR activation. We used microarrays to detail the global programme of gene expression in [METKO + EGFRi] mice liver following TCPOBOP treatment
2018-08-28 | GSE110695 | GEO
Project description:SILAC based protein correlation profiling using size exclusion of protein complexes derived from Mus musculus tissues (Heart, Liver, Lung, Kidney, Skeletal Muscle, Thymus)
2021-05-05 | PXD022309 | Pride
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
| S-EPMC8784167 | biostudies-literature
Project description:SILAC based protein correlation profiling using size exclusion of protein complexes derived from seven Mus musculus tissues (Heart, Brain, Liver, Lung, Kidney, Skeletal Muscle, Thymus)
2018-04-24 | PXD007288 | Pride
Project description:Translational research is commonly performed in the C57B6/J mouse strain, chosen for its genetic homogeneity and phenotypic uniformity. Here, we evaluate the suitability of the white-footed deer mouse (Peromyscus leucopus) as a model organism for aging research, offering a comparative analysis against C57B6/J and diversity outbred (DO) Mus musculus strains. Our study includes comparisons of body composition, skeletal muscle function, and cardiovascular parameters, shedding light on potential applications and limitations of P. leucopus in aging studies. Notably, P. leucopus exhibits distinct body composition characteristics, emphasizing reduced muscle force exertion and a unique metabolism, particularly in fat mass. Cardiovascular assessments showed changes in arterial stiffness, challenging conventional assumptions and highlighting the need for a nuanced interpretation of aging-related phenotypes. Our study also highlights inherent challenges associated with maintaining and phenotyping P. leucopus cohorts. Behavioral considerations, including anxiety-induced responses during handling and phenotyping assessment, pose obstacles in acquiring meaningful data. Moreover, the unique anatomy of P. leucopus necessitates careful adaptation of protocols designed for Mus musculus. While showcasing potential benefits, further extensive analyses across broader age ranges and larger cohorts are necessary to establish the reliability of P. leucopus as a robust and translatable model for aging studies.
| S-EPMC11335981 | biostudies-literature
Project description:EGFR is a critical regulator of hepatocyte proliferation and liver regeneration. Our recent work indicated EGFR can also regulate lipid metabolism during liver regeneration after partial-hepatectomy. Based on these findings, we investigated role of EGFR in a mouse model of NAFLD utilizing a pharmacological inhibition strategy. C57BL6/J mice were fed chow-diet, or fast-food diet with/without EGFR inhibitor (Canertinib) for 2-months. EGFR inhibition completely prevented development of steatosis and liver injury in this model. In order to study if EGFR inhibition can reverse NAFLD progression, mice were fed fast-food diet for 5-months, with/without Canertinib-treatment for the last 5-weeks of the study. EGFR-inhibition remarkably decreased steatosis, liver injury, fibrosis and improved glucose tolerance. Microarray analysis revealed ~40% of genes altered by fast-food diet were differentially expressed after EGFR-inhibition, and thus, are potentially regulated by EGFR. Several genes and enzymes related to lipid metabolism (particularly fatty-acid synthesis and lipolysis), which were disrupted by fast-food diet, were found to be modulated by EGFR. Several crucial transcription factors that play a central role in regulating these lipid metabolism genes during NAFLD, including PPARγ, SREBF1, ChREBP and HNF4α, were also found to be modulated by EGFR. In fact, ChIP-analysis revealed PPARγ binding to several crucial lipid metabolisms genes (Fasn, Scd1 and Plin2) was drastically reduced by EGFR inhibition. Further upstream, EGFR-inhibition suppressed AKT signaling, which is known to control these transcription factors, including PPARγ and SREBF1, in NAFLD models. Lastly, the effect of EGFR in FFD-induced fatty-liver phenotype was not shared by receptor-tyrosine-kinase MET, as investigated using MET-KO mice. In-conclusion, our study revealed a role of EGFR in NAFLD and the potential of EGFR-inhibition as a treatment strategy for NAFLD. We used microarrays to detail the global programme of gene expression in liver of C57BL6/J mice fed fast-food diet mice treated with EGFR inhibitor (canertinib)
2020-05-02 | GSE130528 | GEO
Project description:BackgroundCopy number variation is an important dimension of genetic diversity and has implications in development and disease. As an important model organism, the mouse is a prime candidate for copy number variant (CNV) characterization, but this has yet to be completed for a large sample size. Here we report CNV analysis of publicly available, high-density microarray data files for 351 mouse tail samples, including 290 mice that had not been characterized for CNVs previously.ResultsWe found 9634 putative autosomal CNVs across the samples affecting 6.87% of the mouse reference genome. We find significant differences in the degree of CNV uniqueness (single sample occurrence) and the nature of CNV-gene overlap between wild-caught mice and classical laboratory strains. CNV-gene overlap was associated with lipid metabolism, pheromone response and olfaction compared to immunity, carbohydrate metabolism and amino-acid metabolism for wild-caught mice and classical laboratory strains, respectively. Using two subspecies of wild-caught Mus musculus, we identified putative CNVs unique to those subspecies and show this diversity is better captured by wild-derived laboratory strains than by the classical laboratory strains. A total of 9 genic copy number variable regions (CNVRs) were selected for experimental confirmation by droplet digital PCR (ddPCR).ConclusionThe analysis we present is a comprehensive, genome-wide analysis of CNVs in Mus musculus, which increases the number of known variants in the species and will accelerate the identification of novel variants in future studies.
| S-EPMC4490682 | biostudies-literature