Aristaless-related homeobox plays a key role in hyperplasia of the pancreas islet α-like cells in mice deficient in proglucagon-derived peptides.
Aristaless-related homeobox plays a key role in hyperplasia of the pancreas islet α-like cells in mice deficient in proglucagon-derived peptides.
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DOI：
10.1371/journal.pone.0064415
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Murata Y
中科院分区：
文献类型：
--
作者：
Xu S;Hayashi Y;Takagishi Y;Itoh M;Murata Y
胰高血糖素作用缺陷可引起胰岛α-细胞增生，但其潜在机制仍有待阐明。胰高血糖素- gfp敲入等位基因（Gcggfp/gfp）纯合的小鼠完全缺乏胰高血糖素原衍生肽，并表现出gfp阳性α样细胞的增生。转录因子，马兜铃相关同源盒（ARX）的表达也在Gcggfp/gfp胰腺中增加。在这里，我们试图通过分析两个ARX突变等位基因（ArxP355L/Y和ARX [330insGCG]7/Y）的不同程度的功能损伤来阐明ARX在α样细胞增生中的作用。与Gcggfp/+胰腺相比，Gfp / Gfp胰腺中Gfp和Arx基因的表达在2周龄时更高，胰岛的大小和数量增加。在雄性Gcggfp/gfp小鼠中，由于ArxP355L/Y突变导致蛋白质中P355L氨基酸的替换，胰腺中gfp mRNA的表达与对照Gcggfp/+Arx+/Y小鼠相当。在这些小鼠中，胰岛大小和数量的增加也减少了。免疫组化分析显示gfp阳性细胞数量在Gcggfp/gfp ArxP355L/Y和Gcggfp/+Arx+/Y小鼠中相当。这些结果表明，通过引入Arx突变，增生减少。ArxP355L/Y小鼠表现为表型正常；然而，Arx [330insGCG]7/Y突变型小鼠的体型减小，寿命缩短。Gcggfp/ GFP Arx [330insGCG]7/Y小鼠中GFP阳性细胞数量进一步减少。综上所述，我们的研究结果表明，在胰高血糖素原衍生肽缺失的情况下，ARX的功能是胰岛α样细胞增生的关键修饰因子之一。
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 (Gcggfp/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 Gcggfp/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 (ArxP355L/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 Gcggfp/gfp pancreas compared to and Gcggfp/+ pancreas at 2 weeks of age. In male Gcggfp/gfp mice that are hemizygous for the ArxP355L/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 Gcggfp/+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 Gcggfp/gfp ArxP355L/Y and Gcggfp/+Arx+/Y mice. These results indicate that the hyperplasia is reduced by introduction of an Arx mutation. ArxP355L/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 Gcggfp/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.
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影响因子：
7.7
作者：
Fukami A;Seino Y;Ozaki N;Yamamoto M;Sugiyama C;Sakamoto-Miura E;Himeno T;Takagishi Y;Tsunekawa S;Ali S;Drucker DJ;Murata Y;Seino Y;Oiso Y;Hayashi Y
通讯作者：
Hayashi Y
影响因子：
3.5
作者：
Kitamura, Kunio;Itou, Yukiko;Goto, Yu-ichi
通讯作者：
Goto, Yu-ichi
影响因子：
2.9
作者：
Zhou C;Dhall D;Nissen NN;Chen CR;Yu R
通讯作者：
Yu R
影响因子：
3.7
作者：
Sugiyama C;Yamamoto M;Kotani T;Kikkawa F;Murata Y;Hayashi Y
通讯作者：
Hayashi Y
DOI：
10.1073/pnas.94.13.6646
发表时间：
1997-06-24
影响因子：
11.1
作者：
Furuta, M;Yano, H;Steiner, DF
通讯作者：
Steiner, DF