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Project description:Glucose homeostasis is dependent on functional pancreatic α and ß cells. Mechanisms underlying generation and maturation of these endocrine cells remain unclear. Here, we unravel the molecular mode of action of ISL1 in controlling α cell fate and endocrine differentiation in the pancreas. By combining transgenic mouse models, transcriptomic and epigenomic profiling, we uncover that elimination of Isl1 results in a diabetic phenotype with a complete loss of α cells, disrupted pancreatic islet architecture, downregulation of maturation markers of ß cells, and an enrichment in an intermediate endocrine progenitor transcriptomic profile. Mechanistically, apart from the altered transcriptome of pancreatic endocrine cells, Isl1 elimination results in altered silencing H3K27me3 histone modifications in the promoter regions of the essential genes for endocrine cell differentiation. Our results thus show that ISL1 transcriptionally and epigenetically controls α cell fate competence, and ß cell maturation, suggesting that ISL1 is a critical component for generating functional α and ß cells.
2022-06-17 | GSE206093 | GEO
Project description:Glucose homeostasis is dependent on functional pancreatic α and ß cells. Mechanisms underlying generation and maturation of these endocrine cells remain unclear. Here, we unravel the molecular mode of action of ISL1 in controlling α cell fate and endocrine differentiation in the pancreas. By combining transgenic mouse models, transcriptomic and epigenomic profiling, we uncover that elimination of Isl1 results in a diabetic phenotype with a complete loss of α cells, disrupted pancreatic islet architecture, downregulation of maturation markers of ß cells, and an enrichment in an intermediate endocrine progenitor transcriptomic profile. Mechanistically, apart from the altered transcriptome of pancreatic endocrine cells, Isl1 elimination results in altered silencing H3K27me3 histone modifications in the promoter regions of the essential genes for endocrine cell differentiation. Our results thus show that ISL1 transcriptionally and epigenetically controls α cell fate competence, and ß cell maturation, suggesting that ISL1 is a critical component for generating functional α and ß cells.
2022-06-17 | GSE206092 | GEO
Project description:ISL1 controls pancreatic alpha cell fate and regulates beta cell differentiation and maturation
| PRJNA849181 | ENA
Project description:ISL1 controls pancreatic alpha cell fate and regulates beta cell differentiation and maturation [CUT&Tag]
| PRJNA849186 | ENA
Project description:ISL1 controls pancreatic alpha cell fate and regulates beta cell differentiation and maturation [RNA-seq]
| PRJNA849187 | ENA
Project description:Planar cell polarity (PCP) refers to the collective orientation of cells within the epithelial plane. We show that progenitor cells forming the ducts of the embryonic pancreas express PCP proteins and exhibit an active PCP pathway. Planar polarity proteins are acquired at embryonic day 11.5 synchronously to apicobasal polarization of pancreas progenitors. Loss of function of the two PCP core components Celsr2 and Celsr3 shows that they control the differentiation of endocrine cells from polarized progenitors, with a prevalent effect on insulin-producing beta cells. This results in a decreased glucose clearance. Loss of Celsr2 and 3 leads to a reduction of Jun phosphorylation in progenitors, which, in turn, reduces beta cell differentiation from endocrine progenitors. These results highlight the importance of the PCP pathway in cell differentiation in vertebrates. In addition, they reveal that tridimensional organization and collective communication of cells are needed in the pancreatic epithelium in order to generate appropriate numbers of endocrine cells.
| S-EPMC3606931 | biostudies-literature
Project description:Regulation of multipotent cardiac progenitor cell (CPC) expansion and subsequent differentiation into cardiomyocytes, smooth muscle or endothelial cells is a fundamental aspect of basic cardiovascular biology and cardiac regenerative medicine. However, the mechanisms governing these decisions remain unclear. Here, we show that Wnt/beta-catenin signalling, which promotes expansion of CPCs, is negatively regulated by Notch1-mediated control of phosphorylated beta-catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and beta-catenin negatively, regulated expression of the cardiac transcription factors, Isl1, Myocd and Smyd1. Surprisingly, disruption of Isl1, normally expressed transiently in CPCs before their differentiation, resulted in expansion of CPCs in vivo and in an embryonic stem (ES) cell system. Furthermore, Isl1 was required for CPC differentiation into cardiomyocyte and smooth muscle cells, but not endothelial cells. These findings reveal a regulatory network controlling CPC expansion and cell fate that involves unanticipated functions of beta-catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs.
| S-EPMC2748816 | biostudies-literature
Project description:BACKGROUND: Islet 1 (ISL1), a LIM-homeodomain transcription factor is essential for promoting pancreatic islets proliferation and maintaining endocrine cells survival in embryonic and postnatal pancreatic islets. However, how ISL1 exerts the role in adult islets is, to date, not clear. METHODOLOGY/PRINCIPAL FINDINGS: Our results show that ISL1 expression was up-regulated at the mRNA level both in cultured pancreatic cells undergoing glucose oxidase stimulation as well in type 1 and type 2 diabetes mouse models. The knockdown of ISL1 expression increased the apoptosis level of HIT-T15 pancreatic islet cells. Using HIT-T15 and primary adult islet cells as cell models, we show that ISL1 promoted adult pancreatic islet cell proliferation with increased c-Myc and CyclinD1 transcription, while knockdown of ISL1 increased the proportion of cells in G(1) phase and decreased the proportion of cells in G(2)/M and S phases. Further investigation shows that ISL1 activated both c-Myc and CyclinD1 transcription through direct binding on their promoters. CONCLUSIONS/SIGNIFICANCE: ISL1 promoted adult pancreatic islet cell proliferation and probably by activating c-Myc and CyclinD1 transcription through direct binding on their promoters. Our findings extend the knowledge about the crucial role of ISL1 in maintaining mature islet cells homeostasis. Our results also provide insights into the new regulation relationships between ISL1 and other growth factors.
| S-EPMC3150357 | biostudies-other
Project description:ObjectiveRecent evidence indicates that low oxygen tension (pO2) or hypoxia controls the differentiation of several cell types during development. Variations of pO2 are mediated through the hypoxia-inducible factor (HIF), a crucial mediator of the adaptative response of cells to hypoxia. The aim of this study was to investigate the role of pO2 in beta-cell differentiation.Research design and methodsWe analyzed the capacity of beta-cell differentiation in the rat embryonic pancreas using two in vitro assays. Pancreata were cultured either in collagen or on a filter at the air/liquid interface with various pO2. An inhibitor of the prolyl hydroxylases, dimethyloxaloylglycine (DMOG), was used to stabilize HIF1alpha protein in normoxia.ResultsWhen cultured in collagen, embryonic pancreatic cells were hypoxic and expressed HIF1alpha and rare beta-cells differentiated. In pancreata cultured on filter (normoxia), HIF1alpha expression decreased and numerous beta-cells developed. During pancreas development, HIF1alpha levels were elevated at early stages and decreased with time. To determine the effect of pO2 on beta-cell differentiation, pancreata were cultured in collagen at increasing concentrations of O2. Such conditions repressed HIF1alpha expression, fostered development of Ngn3-positive endocrine progenitors, and induced beta-cell differentiation by O2 in a dose-dependent manner. By contrast, forced expression of HIF1alpha in normoxia using DMOG repressed Ngn3 expression and blocked beta-cell development. Finally, hypoxia requires hairy and enhancer of split (HES)1 expression to repress beta-cell differentiation.ConclusionsThese data demonstrate that beta-cell differentiation is controlled by pO2 through HIF1alpha. Modifying pO2 should now be tested in protocols aiming to differentiate beta-cells from embryonic stem cells.
| S-EPMC2828660 | biostudies-literature
Project description:Glis3 is expressed in pancreatic beta and PP cells. To identify down stream target genes of Glis3, we performed microarray analysis using pancreas total RNAs from 1 week-old WT and Glis3KO2 mice. insulin and pancreatic polypeptide (Ppy) was significantly decreased together with several other β cell markers, Glut2 and MafA by microarray analysis. Immunohistochemistry, QRT-PCR, and transmission electron microscopy indicated that postnatal Glis3KO2 pancreas still contains a large population of β cells that express Pdx-1, Nkx6.1, and Isl-1; however, insulin production and secretory granules were greatly reduced in these cells. In addition, chromogranin A (ChgA) and Urocortin 3, which are associated with mature β cells, was dramatically decreased in Glis3KO2 pancreas. These observations suggest that Glis3 plays a critical role in the maturation of pancreatic β cell phenotype. Pancreatic total RNAs were purified from 4 WT and 4 Glis3KO2 at 1 week old age. Then the samples were applied to Agilent mouse genome chip.
2016-07-01 | E-GEOD-67238 | biostudies-arrayexpress