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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994953/ https://www.ncbi.nlm.nih.gov/pubmed/24487024 http://dx.doi.org/10.2337/db13-0867 |
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author | Metzger, David E. Liu, Chengyang Ziaie, Amin Sam Naji, Ali Zaret, Kenneth S. |
author_facet | Metzger, David E. Liu, Chengyang Ziaie, Amin Sam Naji, Ali Zaret, Kenneth S. |
author_sort | Metzger, David E. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-3994953 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-39949532015-05-01 Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions Metzger, David E. Liu, Chengyang Ziaie, Amin Sam Naji, Ali Zaret, Kenneth S. Diabetes Genetics/Genomes/Proteomics/Metabolomics 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. American Diabetes Association 2014-05 2014-04-12 /pmc/articles/PMC3994953/ /pubmed/24487024 http://dx.doi.org/10.2337/db13-0867 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Genetics/Genomes/Proteomics/Metabolomics Metzger, David E. Liu, Chengyang Ziaie, Amin Sam Naji, Ali Zaret, Kenneth S. Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions |
title | Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions |
title_full | Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions |
title_fullStr | Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions |
title_full_unstemmed | Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions |
title_short | Grg3/TLE3 and Grg1/TLE1 Induce Monohormonal Pancreatic β-Cells While Repressing α-Cell Functions |
title_sort | grg3/tle3 and grg1/tle1 induce monohormonal pancreatic β-cells while repressing α-cell functions |
topic | Genetics/Genomes/Proteomics/Metabolomics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994953/ https://www.ncbi.nlm.nih.gov/pubmed/24487024 http://dx.doi.org/10.2337/db13-0867 |
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