Aristaless-related homeobox plays a key role in hyperplasia of the pancreas islet α-like cells in mice deficient in proglucagon-derived peptides.

Abstract

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.

• Authors: Sai Xu, Yoshitaka Hayashi, Yoshiko Takagishi, Mariko Itoh, Yoshiharu Murata
• Journal: PloS one (PLoS One) Vol. 8 Issue 5 Pg. e64415 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23671715 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARX protein, mouse
• Blood Glucose
• Homeodomain Proteins
• Peptides
• Transcription Factors
• Green Fluorescent Proteins
• Proglucagon
• Glucagon

Topics

• Animals
• Blood Glucose (metabolism)
• Body Weight
• Female
• Gene Expression
• Glucagon (genetics, metabolism)
• Green Fluorescent Proteins (genetics, metabolism)
• Homeodomain Proteins (genetics, metabolism)
• Hyperplasia
• Immunohistochemistry
• Islets of Langerhans (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Microscopy, Fluorescence
• Mutation
• Peptides (genetics, metabolism)
• Proglucagon (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factors (genetics, metabolism)