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Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides
Defects in glucagon action can cause hyperplasia of islet α-cells, however, the underlying mechanisms remain largely to be elucidated. Mice homozygous for a glucagon-GFP knock-in allele (Gcg(gfp/gfp)) completely lack proglucagon-derived peptides and exhibit hyperplasia of GFP-positive α-like cells....
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650067/ https://www.ncbi.nlm.nih.gov/pubmed/23671715 http://dx.doi.org/10.1371/journal.pone.0064415 |
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author | Xu, Sai Hayashi, Yoshitaka Takagishi, Yoshiko Itoh, Mariko Murata, Yoshiharu |
author_facet | Xu, Sai Hayashi, Yoshitaka Takagishi, Yoshiko Itoh, Mariko Murata, Yoshiharu |
author_sort | Xu, Sai |
collection | PubMed |
description | Defects in glucagon action can cause hyperplasia of islet α-cells, however, the underlying mechanisms remain largely to be elucidated. Mice homozygous for a glucagon-GFP knock-in allele (Gcg(gfp/gfp)) completely lack proglucagon-derived peptides and exhibit hyperplasia of GFP-positive α-like cells. Expression of the transcription factor, aristaless-related homeobox (ARX), is also increased in the Gcg(gfp/gfp) pancreas. Here, we sought to elucidate the role of ARX in the hyperplasia of α-like cells through analyses of two Arx mutant alleles (Arx(P355L/Y) and Arx( [330insGCG]7/Y)) that have different levels of impairment of their function. Expression of Gfp and Arx genes was higher and the size and number of islets increased in the Gcg(gfp/gfp) pancreas compared to and Gcg(gfp/+) pancreas at 2 weeks of age. In male Gcg(gfp/gfp) mice that are hemizygous for the Arx(P355L/Y) mutation that results in a protein with a P355L amino acid substitution, expression of Gfp mRNA in the pancreas was comparable to that in control Gcg(gfp/+)Arx(+/Y) mice. The increases in islet size and number were also reduced in these mice. Immunohistochemical analysis showed that the number of GFP-positive cells was comparable in Gcg(gfp/gfp) Arx(P355L/Y) and Gcg(gfp/+)Arx(+/Y) mice. These results indicate that the hyperplasia is reduced by introduction of an Arx mutation. Arx(P355L/Y) mice appeared to be phenotypically normal; however, Arx( [330insGCG]7/Y) mice that have a mutant ARX protein with expansion of the polyalanine tract had a reduced body size and shortened life span. The number of GFP positive cells was further reduced in the Gcg(gfp/gfp) Arx( [330insGCG]7/Y) mice. Taken together, our findings show that the function of ARX is one of the key modifiers for hyperplasia of islet α-like cells in the absence of proglucagon-derived peptides. |
format | Online Article Text |
id | pubmed-3650067 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36500672013-05-13 Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides Xu, Sai Hayashi, Yoshitaka Takagishi, Yoshiko Itoh, Mariko Murata, Yoshiharu PLoS One Research Article Defects in glucagon action can cause hyperplasia of islet α-cells, however, the underlying mechanisms remain largely to be elucidated. Mice homozygous for a glucagon-GFP knock-in allele (Gcg(gfp/gfp)) completely lack proglucagon-derived peptides and exhibit hyperplasia of GFP-positive α-like cells. Expression of the transcription factor, aristaless-related homeobox (ARX), is also increased in the Gcg(gfp/gfp) pancreas. Here, we sought to elucidate the role of ARX in the hyperplasia of α-like cells through analyses of two Arx mutant alleles (Arx(P355L/Y) and Arx( [330insGCG]7/Y)) that have different levels of impairment of their function. Expression of Gfp and Arx genes was higher and the size and number of islets increased in the Gcg(gfp/gfp) pancreas compared to and Gcg(gfp/+) pancreas at 2 weeks of age. In male Gcg(gfp/gfp) mice that are hemizygous for the Arx(P355L/Y) mutation that results in a protein with a P355L amino acid substitution, expression of Gfp mRNA in the pancreas was comparable to that in control Gcg(gfp/+)Arx(+/Y) mice. The increases in islet size and number were also reduced in these mice. Immunohistochemical analysis showed that the number of GFP-positive cells was comparable in Gcg(gfp/gfp) Arx(P355L/Y) and Gcg(gfp/+)Arx(+/Y) mice. These results indicate that the hyperplasia is reduced by introduction of an Arx mutation. Arx(P355L/Y) mice appeared to be phenotypically normal; however, Arx( [330insGCG]7/Y) mice that have a mutant ARX protein with expansion of the polyalanine tract had a reduced body size and shortened life span. The number of GFP positive cells was further reduced in the Gcg(gfp/gfp) Arx( [330insGCG]7/Y) mice. Taken together, our findings show that the function of ARX is one of the key modifiers for hyperplasia of islet α-like cells in the absence of proglucagon-derived peptides. Public Library of Science 2013-05-09 /pmc/articles/PMC3650067/ /pubmed/23671715 http://dx.doi.org/10.1371/journal.pone.0064415 Text en © 2013 Xu et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Xu, Sai Hayashi, Yoshitaka Takagishi, Yoshiko Itoh, Mariko Murata, Yoshiharu Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides |
title | Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides |
title_full | Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides |
title_fullStr | Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides |
title_full_unstemmed | Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides |
title_short | Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides |
title_sort | aristaless-related homeobox plays a key role in hyperplasia of the pancreas islet α–like cells in mice deficient in proglucagon-derived peptides |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650067/ https://www.ncbi.nlm.nih.gov/pubmed/23671715 http://dx.doi.org/10.1371/journal.pone.0064415 |
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