Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Metzger, David E., Liu, Chengyang, Ziaie, Amin Sam, Naji, Ali, Zaret, Kenneth S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
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
_version_ 1782312804156440576
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
work_keys_str_mv AT metzgerdavide grg3tle3andgrg1tle1inducemonohormonalpancreaticbcellswhilerepressingacellfunctions
AT liuchengyang grg3tle3andgrg1tle1inducemonohormonalpancreaticbcellswhilerepressingacellfunctions
AT ziaieaminsam grg3tle3andgrg1tle1inducemonohormonalpancreaticbcellswhilerepressingacellfunctions
AT najiali grg3tle3andgrg1tle1inducemonohormonalpancreaticbcellswhilerepressingacellfunctions
AT zaretkenneths grg3tle3andgrg1tle1inducemonohormonalpancreaticbcellswhilerepressingacellfunctions