| First Author | Xu S | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 5 | Pages | e64415 |
| PubMed ID | 23671715 | Mgi Jnum | J:200861 |
| Mgi Id | MGI:5509428 | Doi | 10.1371/journal.pone.0064415 |
| Citation | Xu S, et al. (2013) Aristaless-related homeobox plays a key role in hyperplasia of the pancreas islet alpha-like cells in mice deficient in proglucagon-derived peptides. PLoS One 8(5):e64415 |
| abstractText | Defects in glucagon action can cause hyperplasia of islet alpha-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 alpha-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 alpha-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 alpha-like cells in the absence of proglucagon-derived peptides. |
