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Pdx1 maintains β-cell identity and function by repressing an α-cell program

ABSTRACT: To get a more complete picture of the transcriptional changes associated with Pdx1 loss in β-cells, we conducted an mRNA microarray comparing normal islet β-cells and a-cells to the reprogrammed cells from PKO mice. Islet beta cells are from mice which has a single copy of Pdx1 flox (Pdx1L/+) allele, but is considered normal based on normal islet morphology, gene profiling, and euglycemic status. We chose to use heterozygous mice as control to avoid the litter effect. Islet alpha cells are from normal mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE52258 | GEO | 2013/11/19

SECONDARY ACCESSION(S): PRJNA227298

REPOSITORIES: GEO

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Pdx1 maintains ?-cell identity and function by repressing an ?-cell program

Project description:To get a more complete picture of the transcriptional changes associated with Pdx1 loss in ?-cells, we conducted an mRNA microarray comparing normal islet ?-cells and a-cells to the reprogrammed cells from PKO mice. Islet beta cells are from mice which has a single copy of Pdx1 flox (Pdx1L/+) allele, but is considered normal based on normal islet morphology, gene profiling, and euglycemic status. We chose to use heterozygous mice as control to avoid the litter effect. Islet alpha cells are from normal mice. To enrich for genes directly affected by Pdx1 loss, we chose the early time-point for analysis of PKO mice (5d after TAM administration). Control mRNA profiling was performed on FACS sorted islet YFP+ ?-cells and a-cells obtained from 2 month-old glucagon-Cre; RosaYFP and RIP-CreER; Pdx1fl/+, RosaYFP mice, respectively.

2013-11-19 | E-GEOD-52258 | biostudies-arrayexpress

scRNA-seq of pancreatic islets from control and Haster-pKO mice

Project description:Pancreas specific deletion of the Haster promoter region results in a variegated phenotype in pancreatic islets with overexpression or silencing of the Hnf1a gene. To determine the transcriptional consequence of the overexpression or silencing of Hnf1a is islet cells from the Haster pKO mice (Haster loxP/loxP;Pdx1-Cre), we performed scRNA-seq of pancreatic islets from control and adult female Haster pKO mice.

2022-05-01 | E-MTAB-11477 | biostudies-arrayexpress

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Project description:Remarkable advancements in protocol development have been achieved to manufacture insulin-secreting islets from human pluripotent stem cells. Distinct from current approaches, we devised a tunable strategy to generate islet spheroids enriched for major islet cell types by incorporating PDX1+ cell budding morphogenesis into the differentiation process of staged transcriptional programming. In this process that appears to mimic normal islet morphogenesis, the differentiating islet spheroids self-organize with endocrine cells that are intermingled or arranged in a core-mantle architecture, accompanied with functional heterogeneity. Through in vitro modelling of human pancreas development, we illustrate the importance of PDX1 in eliciting cell budding morphogenesis, and the requirement for EphB3/4 signaling. We show how RFX6 deficiency affects pancreatic patterning and uncover an expected role of RFX6 in early pancreas morphology. The tunable differentiation system and stem cell-derived islet models described in this work may facilitate addressing fundamental questions in islet biology and probing human pancreas diseases.

2024-05-15 | GSE249020 | GEO

The Pdx1 bound Swi/Snf chromatin remodeling complex regulates pancreatic progenitor cell proliferation and mature islet β cell function

Project description:Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β cell function are controlled by the ATP-dependent Swi/Snf chromatin-remodeling coregulatory complex that physically associates with Pdx1, a diabetes-linked transcription factor essential to pancreatic morphogenesis and adult islet-cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, were required to compromise adult islet β cell activity, which included whole animal glucose intolerance, hyperglycemia and impaired insulin secretion. Notably, lineage-tracing analysis revealed that these Swi/Snf deficient β cells lost the ability to produce insulin and other key metabolic genes, yet the expression levels of many essential islet-enriched transcription factors were unaffected. Swi/Snf was necessary for Pdx1 binding to the insulin enhancer, demonstrating the importance of this association in mediating chromatin accessibility. These results illustrate how fundamental the Pdx1:Swi/Snf coregulator complex is in the pancreas and we discuss how disrupting their association could influence Type 1 and Type 2 diabetes susceptibility.

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Expression Profiling Identifies Novel Gene Targets and Functions for Pdx1 in the Duodenum of Mature Mice

2012-01-12 | GSE29048 | GEO

Gene expression analysis between the pancreatic tissues of Pdx1-cre;Kras LSL-G12D and Pdx-cre;KrasLSL-G12D;IKK2/beta F/F mice

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2012-01-24 | E-GEOD-33322 | biostudies-arrayexpress

Expression Profiling Identifies Novel Gene Targets and Functions for Pdx1 in the Duodenum of Mature Mice

Project description:Transcription factor pancreatic and duodenal homeobox 1 (Pdx1) plays an essential role in the pancreas to regulate its development and maintain proper islet function. However, less is known about the function of Pdx1 in the small intestine. We aim to investigate the role of Pdx1 in mature proximal small intestine by profiling the expression of genes differentially regulated in response to Pdx1 inactivation restricted to the intestinal epithelium in mice. Pdx1 was conditionally inactivated in the intestinal epithelium of Pdx1flox/flox;VilCre mice, by crossing mutant mice homozygous for loxP site-flanked Pdx1 alleles with transgenic mice expressing Cre recombinase under the control of the mouse villin 1 gene promoter. Total RNA was isolated from the first five centimeters of the small intestine from adult Pdx1flox/flox;VilCre and littermate control mice. Microarray analysis was performed to investigate genome-wide transcriptional profiles in the proximal small intestine.

2012-01-12 | E-GEOD-29048 | biostudies-arrayexpress

Pdx1 overexpression sensitizes to IL-1b-induced apoptosis

Project description:Cytokines have been shown to play a key role in the destruction of beta cells. In the rat insulinoma cell line (INS-1ab) overexpressing pancreatic duodenum homeobox 1 (Pdx1) increases sensitivity to Interleukin 1b (IL-1b). To elucidate mechanisms of action underlying Pdx1 driven potentiation of beta-cell sensitivity to IL-1β, we performed a microarray analysis of INS-1ab cells with and without Pdx1 overexpression exposed to IL-1β between 2h and 24h.

2012-09-20 | GSE40642 | GEO

Characterization of signaling pathways associated with pancreatic beta-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db miceCharacterization of signaling pathways associated with pancreatic β-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db mice

Project description:To characterize the signaling mechanisms underlying beta-cell dysfunction in db/db mice and their return to a more “normal” beta-cell phenotype, we applied a mass spectrometry-based quantitative phosphophoproteomics and sialiomics(sialylated N-linked glycopeptides) approach to normal and db/db beta-cells from hyperglycemic and euglycemic environments.

2020-05-19 | PXD017469 | Pride

Expression data from islets of Pdx1-creLate, control and pregnant mice

Project description:ABSTRACT: The human growth hormone (hGH) minigene is frequently used in the derivation of transgenic mouse lines to enhance transgene expression. Although this minigene is present in the transgenes as a secondcistron, and thus not thought to be expressed, we found that three commonly used lines, Pdx1-CreLate, RIP-Cre, and MIP-GFP, each expressed significant amounts of hGH in pancreatic islets. Locally secreted hGH binds to prolactin receptors on β cells, activates STAT5 signaling, and induces pregnancy-like changes in gene expression, thereby augmenting pancreatic β cell mass and insulin content. In addition, islets of Pdx1-CreLate mice have lower GLUT2 expression and reduced glucose-induced insulin release and are protected against the β cell toxin streptozotocin. These findings may be important when interpreting results obtained when these and other hGH minigene-containing transgenic mice are used. Data obtained for the Pdx1-creLate and control samples were compaired to investigate the effect of hGH on the mRNA profile of islets. The data obtained from the islets of pregnant mice was added to the analysis to confirm the pregnacy-like phenotype in the Pdx1-creLate islets. The data of the different days of pregnancy was already described in Schraenen et al. 2010 (PMID: 20886204 and PMID: 20938637).

2014-02-14 | GSE50851 | GEO

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