Mesenchymal Igf2 is a major regulator of pancreatic growth and function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE100981 | GEO | 2017/12/31
SECONDARY ACCESSION(S): PRJNA393571
REPOSITORIES: GEO
Similar Datasets
Project description:The surrounding microenvironment plays a crucial role in pancreas formation and differentiation. Nevertheless, its cellular composition has not been analyzed in depth and whether different cell populations exist within the mesenchyme of the developing pancreas is an open question. Similarly, the molecular mechanisms by which the mesenchyme coordinates and integrates various signaling pathways to stimulate epithelial pancreatic progenitor proliferation and differentiation remain elusive. Here, we investigate the cell composition and molecular network in the pancreatic mesenchyme, which promote pancreas differentiation. Whole transcriptome analysis and functional experiments showed that PBX in the mesenchyme promotes endocrine differentiation non-cell autonomously, acting at two different levels in the epithelial-mesenchymal crosstalk: 1) the maintenance of BM integrity and ECM and 2) regulation of soluble molecules, including guidance cues. In conclusion, this study has identified distinct pancreatic mesenchymal niches and dissected their different roles during pancreatic development. This knowledge will be useful to improve current differentiation strategies based on ECM and soluble factors to generate β-cell equivalents from pluripotent cells for future cell replacement therapies of diabetes.
2020-08-28 | GSE123759 | GEO
Project description:Insulin-like growth factor 2 (Igf2) is the major fetal growth hormone in mammals. Here we identify the Kruppel-associated-box (KRAB) zinc finger protein 568 (ZFP568) as a direct repressor of a placental specific Igf2 transcript (designated Igf2-P0) in early mouse development. Loss of Zfp568, which leads to gastrulation failure, causes inappropriate Igf2-P0 activation. Strikingly, deletion of paternal Igf2 can completely rescue Zfp568 knockout-induced gastrulation phenotypes. Mechanistically, ZFP568 and its binding site are required to maintain H3K9me3 and CpG methylation of the Igf2-P0 region. The ZFP568 binding site upstream of the Igf2-P0 transcript is highly conserved throughout Eutheria, along with the DNA binding domain of ZFP568 orthologs, with the exception of human, whose three Znf568 alleles previously linked to human head size at birth have rapidly evolved and mostly lost the ability to bind and suppress Igf2, coincident with the loss of Igf2-P0 transcript activity. We speculate that the Igf2-P0 transcript and its repressor ZFP568 appeared in a common ancestor of placental mammals as a critical adaptation to boost Igf2 expression specifically in the placenta to regulate maternal supply and fetal demand for nutrients. These data also highlight the exquisite specificity and selectivity by which KRAB-ZFPs have been naturally selected to recognize their genomic targets for pinpoint heterochromatin establishment during mammalian evolution.
2017-05-17 | GSE84832 | GEO
Project description:How organ size and form are controlled during development is a major question of biology. Blood vessels have been shown to be essential for early development of the liver and pancreas, and are fundamental to normal and pathological tissue growth. Here we report that non-nutritional signals from blood vessels surprisingly act to restrain pancreas growth. Elimination of endothelial cells increases the size of embryonic pancreatic buds. Conversely, VEGF-induced hypervascularization decreases pancreas size. The growth phenotype results from vascular restriction of pancreatic tip cell formation, lateral branching and differentiation of the pancreatic epithelium into endocrine and acinar cells. The effects are seen both in vivo and ex vivo, indicating a perfusion-independent mechanism. Thus the vasculature controls pancreas morphogenesis and growth by reducing branching and differentiation of primitive epithelial cells.
2011-09-14 | GSE32098 | GEO
Project description:The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.
2016-09-05 | GSE64073 | GEO
Project description:How organ size and form are controlled during development is a major question of biology. Blood vessels have been shown to be essential for early development of the liver and pancreas, and are fundamental to normal and pathological tissue growth. Here we report that non-nutritional signals from blood vessels surprisingly act to restrain pancreas growth. Elimination of endothelial cells increases the size of embryonic pancreatic buds. Conversely, VEGF-induced hypervascularization decreases pancreas size. The growth phenotype results from vascular restriction of pancreatic tip cell formation, lateral branching and differentiation of the pancreatic epithelium into endocrine and acinar cells. The effects are seen both in vivo and ex vivo, indicating a perfusion-independent mechanism. Thus the vasculature controls pancreas morphogenesis and growth by reducing branching and differentiation of primitive epithelial cells. For transcriptome analysis, RNA was isolated using QIAGEN RNeasy micro Kit from pancreatic buds of Pdx1-tTA (n=3) and littermate Pdx1-tTA; TET-VEGF (n=3) e12.5 embryos, or from e12.5 wild type pancreatic buds explanted and treated with VEGFR2i (n=5) or vehicle (n=5) for 2 days. Pooled samples were hybridized to Affymetrix mouse gene 1.0 st arrays. The arrays were RMA normalized using Partek Genomic Suite 6.5. Differentially regulated genes were selected based on p-values and ratios using t-test.
2011-09-13 | E-GEOD-32098 | biostudies-arrayexpress
Project description:Abstract: Dysregulation of the imprinted H19/IGF2 locus can lead to Silver-Russell Syndrome (SRS) in humans. However, the mechanism of how abnormal H19/IGF2 expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two genes. We previously generated a mouse model with humanized H19/IGF2 ICR (hIC1) on the paternal allele that exhibited H19/Igf2 dysregulation together with SRS-like growth restriction and perinatal lethality. Here we dissect the role of H19 and Igf2 in cardiac and placental development utilizing multiple mouse models with varying levels of H19 and Igf2. We report severe cardiac defects such as ventricular septal defects (VSDs) and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent of H19/Igf2 dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows that H19/Igf2 dysregulation disrupts pathways related to extracellular matrix (ECM) and proliferation of endothelial cells. Our work links the heart and placenta through regulation by H19 and Igf2, demonstrating that accurate dosage of both H19 and Igf2 is critical for normal embryonic development, especially related to the cardiac-placental axis. Methods: E12.5 hearts were lysed with Collagenase, Dispase II, and DNase I. Cardiac endothelial cells were collected using MACS CD31 microbeads and RNA was isolated using RNeasy Micro kit. After confirming RNA integrity using Bioanalyzer, mRNA library was generated from 25ng RNA using NEBNext Poly(A) mRNA Magnetic Isolation Module and Ultra II RNA Library Prep Kit. Library quality was assessed by Bioanalyzer and TapeStation. Sequencing was performed on NovaSeq 6000. Quality of raw fastq reads was assessed using FastQC version 0.11.5. Reads were aligned to the GRCm38/mm10 reference using STAR version 2.4.0i with default parameters and maximum fragment size of 2000 bp. Properly paired primary alignments were retained for downstream analysis using Samtools version 1.9. Count matrices were generated using FeatureCounts version 1.6.2 against RefSeq gene annotation and read into DESeq2 to perform normalization and statistical analysis.
2022-11-25 | GSE199377 | GEO
Project description:Chronic kidney disease (CKD) is prevalent in 10% of world’s adult population, with Estimated Glomerular filtration rate (eGFR) and albuminuria employed in diagnosis. Role of protein glycosylation in causal mechanisms of CKD progression is largely unknown. Aim of this study was to identify urinary O-linked glycopeptides in association to CKD for better characterization of CKD molecular manifestations. Urine samples from 2 healthy and 8 CKD subjects were analyzed by CE-MS/MS and glycopeptide analysis using Proteome Discoverer 1.4. Distribution of identi-fied glycopeptides and correlation with Age, eGFR and Albuminuria were evaluated in 3810 da-tasets. In total, 17 O-linked glycopeptides from 7 different proteins were identified, derived primarily from Insulin-like growth factor-II (IGF2). Glycosylation occurred at the surface ex-posed IGF2 Threonine 96 position. Three glycopeptides (DVStPPTVLPDNFPRYPVGKF, DVStPPTVLPDNFPRYPVG and DVStPPTVLPDNFPRYP) exhibited positive correlation with Age. Glycopeptide (tPPTVLPDNFPRYP) showed strong negative association with eGFR. These results suggest that with aging and deteriorating kidney function, alterations in IGF2 proteoforms take place; which may reflect changes in mature IGF2 protein. Our results corroborate this hypothesis as IGF2 increased plasma levels were observed in CKD patients. Protease predictions, consider-ing also available transcriptomics data, suggest activation of cathepsin S with CKD, meriting further investigation.
2023-05-10 | PXD039829 | Pride
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:We identified an enhancer element near IGF2 locus that is possibly involved with dopamine function and schizophrenia. A knockout mouse was generated for the enhancer element in the IGF2 locus. We then characterized the striatal synaptosomes ( i.e. biological fraction representing pre- post synaptic nerve terminal)by mass spectometry from WT and Igf2 enhancer KO mice.
2019-05-31 | PXD012786 | Pride
Project description:Background & Aims: Hepatocellular carcinoma (HCC) is a major health problem. Most patients are diagnosed at advanced stages when the only approved therapy is sorafenib. Consequently, there is an urgent need to develop effective treatments. IGF-signaling is aberrantly activated in HCC, but there is no clear understanding on the molecular drivers and potential therapeutic targets within the pathway. Since IGF2-ligand is overexpressed in HCC, we aimed to elucidate its mechanism of overexpression, assess its oncogenic potential in vitro and in vivo and determine the antitumoral efficacy of molecular therapies against IGF2. Methods: Expression profiling, miRNAs expression and methylation were analyzed in 228 HCCs focusing on IGF2. Stable HCC cell lines with knock-down and ectopic overexpression of IGF2 were generated. A chemically-induced mouse model of HCC, and genetically-engineered mouse models (GEMM) overexpressing IGF2 in the liver were generated to assess IGF2 oncogenicity. The therapeutic potential of the monoclonal antibody against IGF-ligands (IGF1/2-mAb) and its combination with sorafenib was tested in vitro and in a xenograft model. Results: IGF2-overexpression occurred in 15% of HCC patients as a result of the epigenetic reactivation of IGF2-fetal promoters, mainly through loss of promoter methylation. Re-expression of IGF2 was associated with progenitor cell-like and poorly differentiated HCCs, and with poor prognosis (p<0.0001). In the GEMM model, IGF2-overexpression accelerated HCC progression and reduced survival (p=0.02). Conversely, IGF2-blockage using IGF1/2- mAbs delayed tumor growth and increased survival in vivo (p<0.0001), through antiproliferative and antiangiogenic mechanisms. Conclusions: We propose IGF2 as the first actionable epi-driver in HCC, and IGF1/2-mAbs as a potential targeted therapy in a defined subset of HCC patients. Keywords: IGF2, HCC, epidriver, IGF-pathway, monoclonal antibody, BI 836845.
2019-08-05 | GSE85274 | GEO