Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA153749 | ENA |
REPOSITORIES: ENA
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Project description:During mouse embryogenesis, progenitors within the liver known as hepatoblasts give rise to adult hepatocytes and cholangiocytes. Hepatoblasts, which are specified at E8.5-E9.0, have been regarded as a homogeneous progenitor population that initiate differentiation from E13.5. Recently, scRNA-seq analysis has identified sub- populations of transcriptionally distinct hepatoblasts at E11.5. Here, we show that hepatoblasts are not only transcriptionally but also functionally heterogeneous, and that a subpopulation of E9.5-E10.0 hepatoblasts exhibit a previously unidentified early commitment to cholangiocyte fate. Importantly, we also identify a sub-population constituting 2% of E9.5-E10.0 hepatoblasts that express the adult stem cell marker Lgr5, and generate both hepatocyte and cholangiocyte progeny that persist for the lifespan of the mouse. Combining lineage tracing and scRNA-seq, we show that Lgr5 marks E9.5-E10.0 bipotent liver progenitors residing at the apex of a hepatoblast hierarchy. Notably, isolated Lgr5+ hepatoblasts can be clonally expanded in vitro into embryonic liver organoids, which can commit to either hepatocyte or cholangiocyte fates. Our study demonstrates functional heterogeneity within E9.5 hepatoblasts and identifies Lgr5 as a marker for a sub-population of bipotent liver progenitors.
2019-05-27 | GSE123103 | GEO
Project description:Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. Regulating cell identity requires gene activation and repression. While master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether unwanted plasticity is actively suppressed by lineage-specific repressors. Here, we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that Prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternate fate master regulators. In line with patient data, PROX1 overexpression in mice blocked initiation and progression of hepatocellular carcinoma and extended survival. Remarkably, Prox1 depletion caused hepatocyte fate loss in vitro, and promoted transdifferentiation of hepatocellular- to cholangio-carcinoma in vivo. Our findings provide mechanistic evidence for PROX1 as a hepatocyte-specific safeguard and support a model where individual cell type-specific repressors actively suppress plasticity throughout life to safeguard lineage choice and prevent disease.
2024-11-11 | PXD053043 | Pride
Project description:Cellular binary fate decisions require the progeny to silence genes associated with the alternative fate. The major subsets of alpha:beta T cells have been extensively studied as a model system for fate decisions. While the transcription factor RUNX3 is required for the initiation of Cd4 silencing in CD8 T cell progenitors, it is not required to maintain the silencing of Cd4 and other helper T lineage genes. The other runt domain containing protein, RUNX1, silences Cd4 in an earlier T cell progenitor, but this silencing is reversed whereas the gene silencing after RUNX3 expression is not reverse. Therefore, we hypothesized that RUNX3 and not RUNX1 recruits other factors that maintains the silencing of helper T lineage genes in CD8 T cells. To this end, we performed a proteomics screen of RUNX1 and RUNX3 to determine candidate silencing factors.
2019-11-12 | PXD007511 | Pride
Project description:Understanding how distinct cell types arise from common multipotent progenitor cells is a major quest in stem cell biology. This knowledge will aid in the targeted differentiation and growth of stem cells, but also in the discovery of the basis of cellular plasticity and of how tissue programming can be controlled. The liver and pancreas share many aspects of their early development, being both specified in the same region of the endoderm, and, possibly, originating from a common progenitor. However, how pancreas versus liver cell fate decision occurs during embryogenesis and the molecular basis of this cellular plasticity are poorly understood. Here, we use RNA-Seq to define the molecular identity of liver and pancreas progenitors directly in mouse embryos and to investigate the mechanisms regulating the emergence of liver or pancreas as alternative fates from the endoderm. Progenitor cell-specific RNA was obtained from mouse Prox1-EGFP-labeled embryonic cells isolated by FACS at distinct developmental stages, before and after the onset of organogenesis. By integrating the temporal and spatial gene expression profiles, we found mutually exclusive signaling signatures in hepatic and pancreatic progenitors. Importantly, we identified the non-canonical Wnt pathway as a potential developmental regulator of the pancreas versus liver fate decision, being expressed in the foregut endoderm, before the cell fate choice is made, and then maintained in pancreas progenitors but absent in hepatic progenitors. Moreover, when assayed in Xenopus embryos, the non-canonical Wnt pathway is able to promote pancreatic fate and repress hepatic fate in the endoderm, suggesting an ancient mechanism for controlling pancreas versus liver fate choice. We expect that this knowledge will be key to formulate reprogramming strategies to convert adult hepatic cells into pancreatic cells as a cell-based therapeutic approach for diabetes. We performed sequencing-based expression profiling (RNA-Seq) of hepatic and pancreatic progenitors in the mouse at two distinct developmental stages.
2013-09-11 | E-GEOD-40823 | biostudies-arrayexpress
Project description:The homeobox transcription factor Prox1 is expressed in embryonic hepatoblasts and remains expressed in adult hepatocytes. Prox1-null mice show severe deficiencies of liver development, but the underlying mechanisms are unknown. We studied the effects of Prox1 on the transcriptional profile of embryonic day-14 (ED14) met-murine-hepatocytes (ED14-MMH). These immortalized murine hepatoblasts express numerous hepatoblast markers, but not Prox1. We performed stable transfection with Prox1 cDNA, analyzed the transcriptome with Agilent mouse whole genome microarrays and validated genes by qRT-PCR. We observed more than 12-fold up-regulation of 22 genes and down-regulation of 232 genes. Numerous of these genes are involved in metabolic hepatocyte functions and may be regulated by Prox1 directly or indirectly, e.g. by down-regulation of HNF4a. Prox1 induces down-regulation of transcription factors, which are highly expressed in neighboring endodermal organs, suggesting a function during hepatoblast commitment. Prox1 does not influence proliferative activity of MMH but regulates genes involved in liver morphogenesis. We observed up-regulation of both type-IVa3 procollagen and functionally active matrix metalloproteinase-2 (MMP-2), which places Prox1 in the centre of liver matrix turnover. This is consistent with MMP-2 expression in hepatoblasts during liver development, and persistence of a basal lamina around the liver bud in Prox1-deficient mice. Our studies suggest that Prox1 is a multifunctional regulator of liver morphogenesis, hepatocyte function and commitment. Experiment Overall Design: - two samples Experiment Overall Design: - Dye Swap design with 6 arrays
2008-06-15 | E-GEOD-7867 | biostudies-arrayexpress
Project description:We generated intrahepatic cholangiocyte organoids and fetal hepatocyte organoids to compare their transcriptomic profile with liver tissue, primary human hepatocytes, and other hepatocyte model systems.
2022-09-25 | GSE214097 | GEO
Project description:Understanding how distinct cell types arise from common multipotent progenitor cells is a major quest in stem cell biology. This knowledge will aid in the targeted differentiation and growth of stem cells, but also in the discovery of the basis of cellular plasticity and of how tissue programming can be controlled. The liver and pancreas share many aspects of their early development, being both specified in the same region of the endoderm, and, possibly, originating from a common progenitor. However, how pancreas versus liver cell fate decision occurs during embryogenesis and the molecular basis of this cellular plasticity are poorly understood. Here, we use RNA-Seq to define the molecular identity of liver and pancreas progenitors directly in mouse embryos and to investigate the mechanisms regulating the emergence of liver or pancreas as alternative fates from the endoderm. Progenitor cell-specific RNA was obtained from mouse Prox1-EGFP-labeled embryonic cells isolated by FACS at distinct developmental stages, before and after the onset of organogenesis. By integrating the temporal and spatial gene expression profiles, we found mutually exclusive signaling signatures in hepatic and pancreatic progenitors. Importantly, we identified the non-canonical Wnt pathway as a potential developmental regulator of the pancreas versus liver fate decision, being expressed in the foregut endoderm, before the cell fate choice is made, and then maintained in pancreas progenitors but absent in hepatic progenitors. Moreover, when assayed in Xenopus embryos, the non-canonical Wnt pathway is able to promote pancreatic fate and repress hepatic fate in the endoderm, suggesting an ancient mechanism for controlling pancreas versus liver fate choice. We expect that this knowledge will be key to formulate reprogramming strategies to convert adult hepatic cells into pancreatic cells as a cell-based therapeutic approach for diabetes.
2013-09-11 | GSE40823 | 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