RRC ID 21800
Author Xu S, Hayashi Y, Takagishi Y, Itoh M, Murata Y.
Title Aristaless-related homeobox plays a key role in hyperplasia of the pancreas islet α-like cells in mice deficient in proglucagon-derived peptides.
Journal PLoS ONE
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.
Volume 8(5)
Pages e64415
Published 2013
DOI 10.1371/journal.pone.0064415
PII PONE-D-13-05274
PMID 23671715
PMC PMC3650067
MeSH Animals Blood Glucose / metabolism Body Weight Female Gene Expression Glucagon / genetics Glucagon / metabolism Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism Homeodomain Proteins / genetics Homeodomain Proteins / metabolism* Hyperplasia Immunohistochemistry Islets of Langerhans / metabolism* Islets of Langerhans / pathology Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Microscopy, Fluorescence Mutation Peptides / genetics Peptides / metabolism* Proglucagon / genetics Proglucagon / metabolism* Reverse Transcriptase Polymerase Chain Reaction Transcription Factors / genetics Transcription Factors / metabolism*
IF 2.776
Times Cited 0
Mice Arx (GCG)7-1 KI (B6) (RBRC03654) Arx P355L-1 KI (B6) (RBRC03661)