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Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions

In the pancreas, α- and β-cells possess a degree of plasticity. In vitro differentiation of pluripotent cells yields mostly α- and polyhormonal β-like cells, indicating a gap in understanding of how functional monohormonal β-cells are formed and of the endogenous repressive mechanisms used to mainta... Full description

Journal Title: Diabetes 2014, Vol.63(5), p.1804-1816
Main Author: Metzger, David E
Other Authors: Liu, Chengyang , Ziaie, Amin Sam , Naji, Ali , Zaret, Kenneth S
Format: Electronic Article Electronic Article
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ID: ISSN: 0012-1797 ; E-ISSN: 1939-327X ; DOI: 10.2337/db13-0867 ; PMCID: 3994953 ; PMID: 24487024
Link: 1804.pdf
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title: Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions
format: Article
creator:
  • Metzger, David E
  • Liu, Chengyang
  • Ziaie, Amin Sam
  • Naji, Ali
  • Zaret, Kenneth S
subjects:
  • Genetics/Genomes/Proteomics/Metabolomics
ispartof: Diabetes, 2014, Vol.63(5), p.1804-1816
description: In the pancreas, α- and β-cells possess a degree of plasticity. In vitro differentiation of pluripotent cells yields mostly α- and polyhormonal β-like cells, indicating a gap in understanding of how functional monohormonal β-cells are formed and of the endogenous repressive mechanisms used to maintain β-cell identity. We show that the corepressor Grg3 is expressed in almost all β-cells throughout embryogenesis to adulthood. However, Grg3 is expressed in fewer nascent α-cells and is progressively lost from α-cells as endocrine cells mature into adulthood. We show that mouse Grg3 +/− β-cells have increased α-specific gene expression, and Grg3 +/− pancreata have more α-cells and more polyhormonal cells, indicating that Grg3 is required for the physiologic maintenance of monohormonal β-cell identity. Ectopic expression of Grg3 in α-cells represses glucagon and Arx, and the addition of Pdx1 induces Glut2 expression and glucose-responsive insulin secretion. Furthermore, we found that Grg1 is the predominant Groucho expressed in human β-cells but acts functionally similarly to Grg3. Overall, we find that Grg3 and Grg1 establish a monohormonal β-cell identity, and Groucho family members may be useful tools or markers for making functional β-cells.
language:
source:
identifier: ISSN: 0012-1797 ; E-ISSN: 1939-327X ; DOI: 10.2337/db13-0867 ; PMCID: 3994953 ; PMID: 24487024
fulltext: fulltext
issn:
  • 0012-1797
  • 00121797
  • 1939-327X
  • 1939327X
url: Link


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titleGrg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions
creatorMetzger, David E ; Liu, Chengyang ; Ziaie, Amin Sam ; Naji, Ali ; Zaret, Kenneth S
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descriptionIn the pancreas, α- and β-cells possess a degree of plasticity. In vitro differentiation of pluripotent cells yields mostly α- and polyhormonal β-like cells, indicating a gap in understanding of how functional monohormonal β-cells are formed and of the endogenous repressive mechanisms used to maintain β-cell identity. We show that the corepressor Grg3 is expressed in almost all β-cells throughout embryogenesis to adulthood. However, Grg3 is expressed in fewer nascent α-cells and is progressively lost from α-cells as endocrine cells mature into adulthood. We show that mouse Grg3 +/− β-cells have increased α-specific gene expression, and Grg3 +/− pancreata have more α-cells and more polyhormonal cells, indicating that Grg3 is required for the physiologic maintenance of monohormonal β-cell identity. Ectopic expression of Grg3 in α-cells represses glucagon and Arx, and the addition of Pdx1 induces Glut2 expression and glucose-responsive insulin secretion. Furthermore, we found that Grg1 is the predominant Groucho expressed in human β-cells but acts functionally similarly to Grg3. Overall, we find that Grg3 and Grg1 establish a monohormonal β-cell identity, and Groucho family members may be useful tools or markers for making functional β-cells.
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titleGrg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions
descriptionIn the pancreas, α- and β-cells possess a degree of plasticity. In vitro differentiation of pluripotent cells yields mostly α- and polyhormonal β-like cells, indicating a gap in understanding of how functional monohormonal β-cells are formed and of the endogenous repressive mechanisms used to maintain β-cell identity. We show that the corepressor Grg3 is expressed in almost all β-cells throughout embryogenesis to adulthood. However, Grg3 is expressed in fewer nascent α-cells and is progressively lost from α-cells as endocrine cells mature into adulthood. We show that mouse Grg3 +/− β-cells have increased α-specific gene expression, and Grg3 +/− pancreata have more α-cells and more polyhormonal cells, indicating that Grg3 is required for the physiologic maintenance of monohormonal β-cell identity. Ectopic expression of Grg3 in α-cells represses glucagon and Arx, and the addition of Pdx1 induces Glut2 expression and glucose-responsive insulin secretion. Furthermore, we found that Grg1 is the predominant Groucho expressed in human β-cells but acts functionally similarly to Grg3. Overall, we find that Grg3 and Grg1 establish a monohormonal β-cell identity, and Groucho family members may be useful tools or markers for making functional β-cells.
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abstractIn the pancreas, α- and β-cells possess a degree of plasticity. In vitro differentiation of pluripotent cells yields mostly α- and polyhormonal β-like cells, indicating a gap in understanding of how functional monohormonal β-cells are formed and of the endogenous repressive mechanisms used to maintain β-cell identity. We show that the corepressor Grg3 is expressed in almost all β-cells throughout embryogenesis to adulthood. However, Grg3 is expressed in fewer nascent α-cells and is progressively lost from α-cells as endocrine cells mature into adulthood. We show that mouse Grg3 +/− β-cells have increased α-specific gene expression, and Grg3 +/− pancreata have more α-cells and more polyhormonal cells, indicating that Grg3 is required for the physiologic maintenance of monohormonal β-cell identity. Ectopic expression of Grg3 in α-cells represses glucagon and Arx, and the addition of Pdx1 induces Glut2 expression and glucose-responsive insulin secretion. Furthermore, we found that Grg1 is the predominant Groucho expressed in human β-cells but acts functionally similarly to Grg3. Overall, we find that Grg3 and Grg1 establish a monohormonal β-cell identity, and Groucho family members may be useful tools or markers for making functional β-cells.
pubAmerican Diabetes Association
doi10.2337/db13-0867
pmid24487024
pages1804-18016
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date2014-05-00