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Glis3 regulates pancreatic beta cells development and maturation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE67238 | GEO | 2016/07/01

SECONDARY ACCESSION(S): PRJNA279305

REPOSITORIES: GEO

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Glis3 regulates pancreatic beta cells development and maturation

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 Î² 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 Î² 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 Î² cells, was dramatically decreased in Glis3KO2 pancreas. These observations suggest that Glis3 plays a critical role in the maturation of pancreatic Î² 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

Characterization of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice

Project description:Pancreatic polypeptide (PP) cells, which secrete PP encoded by the Ppy gene, is a minor population of endocrine cells in the pancreas. At present, little is known about the characteristics of Ppy-expressing cells. Using a Ppy-Cre driver, here we show that cells of the Ppy lineage contribute to four major types of endocrine cells, including beta cells. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorized into two groups; i.e., Ppy-lineage and non-Ppy-lineage beta cells. These subpopulations of beta cells demonstrated distinct characteristics in terms of functionality and gene expression profiles. Ppy-lineage beta cells are less active in glucose-stimulated calcium signaling, are localized at the periphery of islets, and survive for long periods in experimental diabetes models, and sharing various molecular characteristics with PP cells. Our results indicate the unexpected degree of beta-cell heterogeneity defined by Ppy-gene activation, providing valuable insights into the homeostatic regulation of pancreatic islets, and future therapeutic strategies against diabetes.

2021-07-26 | GSE166164 | GEO

MicroRNA-21 Promotes Pancreatic β cell Function through Modulating Glucose Uptake

Project description:Pancreatic β cell dysfunction greatly contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic β cell function remains largely elusive. In the current study, we studied the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their β cells (miR-21βKO). We found that miR-21βKO mice developed glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies revealed that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets resulted in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrated that delivery of miR-21 into the pancreas of type 2 diabetic db/db mice is able to promote Glut2 expression and significantly reduce blood glucose level. Taking together, our results reveal that miR-21 in islet β cell promotes insulin secretion and support a role for miR-21 in the adaptation of pancreatic β cell function in type 2 diabetes.

2022-05-16 | GSE191194 | GEO

Pancreas-specific Sirt1-deficiency in mice compromises beta-cell function without development of hyperglycemia

Project description:Sirtuin 1 (Sirt1) has been reported to be a critical positive regulator of glucose-stimulated insulin secretion in pancreatic beta-cells. The effects on islet cells and blood glucose levels when Sirt1 is deleted specifically in the pancreas are still unclear.This study examined islet glucose responsiveness, blood glucose levels, pancreatic islet histology and gene expression in Pdx1-Cre;Sirt1(ex4F/F) mice that have loss of function and loss of expression of Sirt1 specifically in the pancreas. We found that in the Pdx1-Cre;Sirt1(ex4F/F) mice, the relative insulin positive area and the islet size distribution were unchanged. However, beta-cells were functionally impaired, presenting with lower glucose-stimulated insulin secretion. This defect was not due to a reduced expression of insulin but was associated with a decreased expression of the glucose transporter Slc2A2/Glut2 and of the Glucagon like peptide-1 receptor (Glp1r) as well as with a marked down regulation of endoplasmic reticulum (ER) chaperones that participate in the Unfolded Protein Response (UPR) pathway. Counter intuitively, the Sirt1-deficient mice did not develop hyperglycemia. Pancreatic polypeptide (PP) cells were the only other islet cells affected, with reduced numbers in the Sirt1-deficient pancreas. This study provides new mechanistic insights showing that beta-cell function in Sirt1-deficient pancreas is affected due to altered glucose sensing and deregulation of the UPR pathway. Interestingly, we uncover a context in which impaired beta-cell function is not accompanied by increased glycemia. This points to a unique compensatory mechanism. Given the reduction in PP, investigation of its role in the control of blood glucose is warranted. To uncover other Sirt1-regulated mechanisms, we performed a gene expression microarray analysis comparing pancreata from the 6 month old Sirt1âdeficient mice to their controls (n=3 per group).

2016-03-01 | E-GEOD-67239 | biostudies-arrayexpress

Induction of insulin gene transcription by Gli-similar KrÃ¼ppel-like zinc finger protein 3, Glis3, in Î±TC1-9 cells

Project description:In this study, we examined the effect of Glis3 on the transcriptional activation of gene expression, including insulin gene, in pancreatic Î±-cell line, Î±TC1-9, which do not express the insulin gene. We demonstrate that Glis3 induces the transcription of the insulin and identified a number of other genes that are induced by Glis3. Using ChIP-Seq we map the genome-wide sites with which Glis3 is associated. From this the consesus Glis3 binding site was calculated. This study shows that Glis3 is recruited to the proximal promoter of the insuln gene inthe pancreatic Î±-cell line, Î±TC1-9.

2016-03-14 | E-GEOD-72566 | biostudies-arrayexpress

T.F. Glis3: a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression

Project description:Glis3 mutant mice (Glis3zf/zf) die within the first week after birth due to overt diabetes, evidenced by hyperglycemia and hypoinsulinemia. Histopathological analysis showed that Glis3zf/zf mice develop a pancreatic phenotype with a dramatic loss of beta- (insulin) and delta- (somatostatin) cells contrasting a smaller relative loss of alpha- (glucagon), PP- (pancreatic polypeptide), and epsilon- (ghrelin) cells. Glis3zf/zf mice develop ductal cysts with decreased number of primary cilia, while the acini are not significantly affected. Gene expression profiling by microarray analysis demonstrated that the expression of terminal hormonal genes and several transcription factors important in endocrine development were significantly deregulated in Glis3zf/zf mice. During pancreatic development, Glis3 mRNA expression is induced during the secondary transition, a stage of cell lineage specification and extensive patterning. Changes in pancreatic development of Glis3zf/zf mice are noted during and after this stage. The population of pancreatic progenitors appears not to be greatly affected in Glis3zf/zf mice; however, the number of neurogenin 3 (Ngn3) positive, endocrine progenitors is significantly reduced. Our study indicates that Glis3 plays a key role in cell lineage specification, particularly the development of mature pancreatic beta-cells. In addition, we identified evidence that Glis3 regulates insulin gene expression through two Glis-binding sites in its proximal promoter indicating that Glis3 is a regulator of insulin gene expression.

2010-01-01 | GSE18172 | GEO

Pancreatic Ppy-expressing gamma-cells display mixed phenotypic traits and adaptive plasticity to engage insulin production

Project description:The cellular identity of pancreatic polypeptide (Ppy)-expressing γ-cells, the rarest pancreatic islet cell-type, remains elusive. Within islets, glucagon and somatostatin, released respectively from α- and δ-cells, modulate the secretion of insulin by β-cells. Dysregulation of insulin production raises blood glucose levels, leading to diabetes onset. Here, we present the genetic signature of human and mouse γ-cells. Using newly developed tools, we identified a set of genes and pathways defining their functional identity. We found that the γ-cell population is heterogeneous, with subsets of cells producing another hormone in addition to Ppy. These bihormonal cells share identity markers typical of the other islet cell-types. In mice, Ppy gene inactivation or conditional γ-cell ablation did not alter glycemia nor body weight. Interestingly, upon β-cell injury induction, γ-cells exhibited gene expression changes and some of them engaged insulin production, like α- and δ-cells. In conclusion, we provide a comprehensive characterization of γ-cells and highlight their plasticity and therapeutic potential.

2021-06-04 | GSE156665 | GEO

Pancreas-specific Sirt1-deficiency in mice compromises beta-cell function without development of hyperglycemia

2016-03-01 | GSE67239 | GEO

A Glis3-CD133-Wnt signaling axis regulating the self-renewal of adult murine pancreatic progenitor-like cells in colonies/organoids

Project description:Adult pancreatic progenitor cells are a potential source of renewable insulin producing cells that can be used in regenerative medicine and cell replacement therapy for type-1 diabetes. We sought to understand the mechanisms by which adult pancreatic progenitor cells undergo self-renewal. The effects of knockdown of Glis3, CD133 (Prominin-1) and beta-catenin were investigated and we found that Glis3 and CD133 are capable of regulating self-renewal through Wnt gene expression.

2019-06-30 | GSE124944 | GEO

Induction of insulin gene transcription by Gli-similar Krüppel-like zinc finger protein 3, Glis3, in αTC1-9 cells

Project description:In this study, we examined the effect of Glis3 on the transcriptional activation of gene expression, including insulin gene, in pancreatic α-cell line, αTC1-9, which do not express the insulin gene. We demonstrate that Glis3 induces the transcription of the insulin and identified a number of other genes that are induced by Glis3.

2016-03-14 | GSE72566 | GEO

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