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

• Published in: PloS one Vol. 8; no. 5; p. e64415
• Main Authors: Xu, Sai, Hayashi, Yoshitaka, Takagishi, Yoshiko, Itoh, Mariko, Murata, Yoshiharu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.05.2013; Public Library of Science (PLoS)
• Subjects: Alleles; Amino acid substitution; Animals; ARX protein; Biology; Blood Glucose - metabolism; Body size; Body Weight; Cell growth; Defects; Diabetes; Environmental health; Female; Gene Expression; Genetics; Glucagon; Glucagon - genetics; Glucagon - metabolism; Glucose; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Homeobox; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Hyperplasia; Immunohistochemistry; Insulin; Intellectual disabilities; Islets of Langerhans; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Laboratory animals; Male; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Fluorescence; Mutation; Pancreas; Peptides; Peptides - genetics; Peptides - metabolism; Polyalanine; Proglucagon - genetics; Proglucagon - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Transcription Factors - genetics; Transcription Factors - metabolism; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0064415

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.