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Discovery of a Drug Candidate for GLIS3-Associated Diabetes

ABSTRACT: Through development and use of a minimal component protocol for derivation of late stage pancreatic progenitors and beta-like cells, we compared WT and GLIS3-/- pancreatic cells at different stages and discovered that GLIS3-/- cells show an ectopic activation of TGF-beta signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114051 | GEO | 2018/05/05

REPOSITORIES: GEO

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Discovery of a Drug Candidate for GLIS3-Associated Diabetes

Project description:Discovery of a Drug Candidate for GLIS3-Associated Diabetes

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Glis3 regulates pancreatic beta cells development and maturation

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Discovery of a drug candidate for GLIS3-associated diabetes.

Project description:GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3-/- β-like cells have been unsuccessful. Here, we develop a "minimal component" protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3-/- hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.

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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.

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Glis3: a critical player in the regulation of pancreatic beta cell development

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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.

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Project description:GLIS3

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

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Identification of SRSF6 splicing regulatory map and its impact on diabetes susceptibility genes regulation

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