Project description:A mouse model for human small cell lung carcinoma (SCLC) has been developed based on evidence in human tumors that the tumor suppressor functions of RB and p53 are defective in more than 90% of SCLC cases. We also developed another mouse model also combines loss of p130 (Rbl2), an RB-related gene, with deletion of RB and p53. These two mouse tumors were shown to closely resemble human SCLC. The goal of this array experiment is to assess genome-wide gene expression of those mouse tumors and determine the similarity of the mouse models to human SCLC. Gene expression from Mouse Rb/p53 ( n=10 ) and Rb/p53/p130 primary tumors ( n=3 ) as well as tumor-free adult mouse lungs ( n=2 ) was measured using the Affymetrix GeneChip Mouse Genome 430-2.0 arrays.
Project description:We have previously reported that the deficiency of p53 alone or in combination with Rb (Rb-/- p53-/-) in adipose-derived MSCs (ASCs) promotes leiomyosarcoma-like tumors in vivo. Here, we hypothesized that the source of MSCs and/or the cell differentiation stage could determine the phenotype of sarcoma development. To investigate whether there is a link between the source of MSCs and sarcoma phenotype, we generated p53-/- and Rb-/-p53-/- MSCs from bone marrow (BM-MSCs). Both genotypes of BM-MSCs initiated leiomyosarcoma formation similar to p53-/- and Rb-/-p53-/- ASCs. In addition, gene expression profiling revealed a link between p53- or Rb-p53-deficient BM-MSCs and ASCs and muscle-associated sarcomagenesis. These data suggest that the tissue source of MSC does not seem a crucial factor in the development of a particular sarcoma phenotype. To analyze whether the differentiation stage defines the sarcoma phenotype, BM-MSCs and ASCs were induced to differentiate towards the osteogenic lineage, and both p53 and Rb were excised using Cre-expressing adenovectors at different stages along osteogenic differentiation. Regardless of the level of osteogenic commitment, the inactivation of Rb and p53 in BM-MSC-derived, but not in ASC-derived, osteogenic progenitors gave rise to osteosarcoma-like tumors which could be serially transplanted. This indicates that the osteogenic differentiation stage of BM-MSCs imposes the phenotype of in vivo sarcoma development, and that BM-MSC-derived osteogenic progenitors rather than undifferentiated BM-MSCs, undifferentiated ASCs or ASC-derived osteogenic progenitors, represent the cell of origin for osteosarcoma development. BM-MSC and ASC cultures were established from 3 mouse strains: (a) WT, (b) p53loxP/loxP and (c) p53loxP/loxP RbloxP/loxP. The corresponding mutant cells were generated by excision of the LoxP-flanked sequences by infection of all MSC cultures with adenoviral vectors expressing the Cre-recombinase gene (Ad-CMV-Cre). NSG mice were inoculated subcutaneously with 5×10^6 mutant cells. Animals were killed when tumors reached 1 cm3 or 150 days after infusion. Some of the obtained tumors were mechanically disaggregated to establish ex vivo MSC-transformed cell lines. Gene expression analysis was performed using BM-MSCs and ASCs from all genotypes, as well as tumor cell lines derived from p53-/- and p53-/-Rb-/- BM-MSC and ASC cultures.
Project description:A mouse model for human small cell lung carcinoma (SCLC) has been developed based on evidence in human tumors that the tumor suppressor functions of RB and p53 are defective in more than 90% of SCLC cases. We also developed another mouse model also combines loss of p130 (Rbl2), an RB-related gene, with deletion of RB and p53. These two mouse tumors were shown to closely resemble human SCLC.
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.
Project description:The aim was to identify pathways and genes that are transcriptionally deregulated in osteosarcoma due to changes in CpG island DNA methylation. In order to identify candidates, we compared low passage cell cultures derived from a mouse model of osteosarcoma to mature osteoblasts derived by in vitro differentiation of the mouse bone marrow stromal cell line, Kusa4b10. Under cell culture osteoblastic differentiating conditions, Kusa4b10 cells acquire a mature osteoblastic phenotype (21 days). A potential role for DNA methylation in directing gene expression changes was established by integrating gene expression data with genome wide DNA methylation maps generated by methyl-DNA binding domain capture and NimbleGen promoter arrays (MBDCap-Chip). 3 cell lines derived from primary tumors from p53 Rb Osterix-Cre:lox OS model, 3 Osteoblasts (differentiated Kusa4b10 cells (21 days under osteoblastic differentiation conditions)
Project description:Next Generation Sequencing Facilitates Quantitative Analysis of s.c. tumors from nude mouse allografted by R728T1 (non-SMCs derived from Rb/P53 mouse model) with and without Taz knockdown
Project description:The aim of the study was to investigate whether the trefoil peptide genes, in concerted action with a miRNA regulatory network, were contributing to nutritional maintrenance. Using a Tff2 knock-out mouse model, 48 specific miRNAs were noted to be significantly deregulated when compared to the wild type strain.
Project description:The aim of the study was to investigate whether the trefoil peptide genes, in concerted action with a miRNA regulatory network, were contributing to nutritional maintrenance. Using a Tff3 knock-out mouse model, 21 specific miRNAs were noted to be significantly deregulated when compared to the wild type strain.
Project description:The goals of this study are to compare the different transcriptome signiture between s.c. tumors from nude mouse allografted by R728T1 (non-SMCs derived from Rb/P53 mouse model)with and without Taz knockdown with NGS-derived retinal transcriptome profiling (RNA-seq).