β-Cell-Specific Mafk Overexpression Impairs Pancreatic Endocrine Cell Development.
β-Cell-Specific Mafk Overexpression Impairs Pancreatic Endocrine Cell Development.
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DOI：
10.1371/journal.pone.0150010
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Takahashi S
中科院分区：
文献类型：
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作者：
Abdellatif AM;Oishi H;Itagaki T;Jung Y;Shawki HH;Okita Y;Hasegawa Y;Suzuki H;El-Morsy SE;El-Sayed MA;Shoaib MB;Sugiyama F;Takahashi S
MAF家族转录因子是禽类逆转录病毒AS42致癌成分v-MAF的同源物。根据它们的结构、功能和分子大小，它们被细分为两类，小的和大的MAF蛋白。MAFK是小MAF家族的成员，是大MAF的主要否定形式。在以前的研究中，我们建立了过表达MAFK的转基因小鼠，以抑制胰腺β细胞中大MAF蛋白的功能。由于葡萄糖刺激的胰岛素分泌受损，这些小鼠在成年后出现高血糖。本研究的目的是研究β细胞特异性MAFK过表达在内分泌细胞发育中的作用。由于β细胞增殖减少，转Mafk基因胚胎的胰岛发育紊乱，胰岛素+和胰升糖素+细胞总数倒置。定量逆转录聚合酶链式反应的基因表达分析显示，β细胞相关基因的表达水平降低，这些基因的表达受大的MAF蛋白控制。此外，这些变化伴随着关键的β细胞转录因子的显著增加，这可能是由于β细胞丢失时可能被激活的代偿机制所致。最后，基因芯片比较了野生型和转基因胰腺的基因表达谱，发现Pcbd1、Fam132a、Cryba2和NPY等未鉴定基因发生了改变，这些基因可能在胰腺内分泌发育过程中起重要作用。综上所述，这些结果表明，MAFK的过度表达通过调节许多β细胞相关基因来损害内分泌发育。微阵列分析提供了一个独特的差异表达基因数据集，这可能有助于更好地理解控制内分泌胰腺发育和功能的分子基础。
The MAF family transcription factors are homologs of v-Maf, the oncogenic component of the avian retrovirus AS42. They are subdivided into 2 groups, small and large MAF proteins, according to their structure, function, and molecular size. MAFK is a member of the small MAF family and acts as a dominant negative form of large MAFs. In previous research we generated transgenic mice that overexpress MAFK in order to suppress the function of large MAF proteins in pancreatic β-cells. These mice developed hyperglycemia in adulthood due to impairment of glucose-stimulated insulin secretion. The aim of the current study is to examine the effects of β-cell-specific Mafk overexpression in endocrine cell development. The developing islets of Mafk-transgenic embryos appeared to be disorganized with an inversion of total numbers of insulin+ and glucagon+ cells due to reduced β-cell proliferation. Gene expression analysis by quantitative RT-PCR revealed decreased levels of β-cell-related genes whose expressions are known to be controlled by large MAF proteins. Additionally, these changes were accompanied with a significant increase in key β-cell transcription factors likely due to compensatory mechanisms that might have been activated in response to the β-cell loss. Finally, microarray comparison of gene expression profiles between wild-type and transgenic pancreata revealed alteration of some uncharacterized genes including Pcbd1, Fam132a, Cryba2, and Npy, which might play important roles during pancreatic endocrine development. Taken together, these results suggest that Mafk overexpression impairs endocrine development through a regulation of numerous β-cell-related genes. The microarray analysis provided a unique data set of differentially expressed genes that might contribute to a better understanding of the molecular basis that governs the development and function of endocrine pancreas.