Shao Weijuan, Xiong Xiaoquan, Ip Wilfred, Xu Fenghao, Song Zhuolun, Zeng Kejing, Hernandez Marcela, Liang Tao, Weng Jianping, Gaisano Herbert, Nostro M Cristina, Jin Tianru
Division of Advanced Diagnostics, Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada.
Institute of Medical Science, University of Toronto, Toronto, ON, M5S 2J7, Canada.
Mol Metab. 2015 Feb 4;4(4):344-52. doi: 10.1016/j.molmet.2015.01.008. eCollection 2015 Apr.
Disruption of TCF7L2 in mouse pancreatic β-cells has generated different outcomes in several investigations. Here we aim to clarify role of β-cell TCF7L2 and Wnt signaling using a functional-knockdown approach.
Adenovirus-mediated dominant negative TCF7L2 (TCF7L2DN) expression was conducted in Ins-1 cells. The fusion gene in which TCF7L2DN expression is driven by P TRE3G was utilized to generate the transgenic mouse line TCF7L2DN Tet . The double transgenic line was created by mating TCF7L2DN Tet with Ins2-rtTA, designated as βTCFDN. β-cell specific TCF7L2DN expression was induced in βTCFDN by doxycycline feeding.
TCF7L2DN expression in Ins-1 cells reduced GSIS, cell proliferation and expression of a battery of genes including incretin receptors and β-cell transcription factors. Inducing TCF7L2DN expression in βTCFDN during adulthood or immediately after weaning generated no or very modest metabolic defect, while its expression during embryonic development by doxycycline feeding in pregnant mothers resulted in significant glucose intolerance associated with altered β-cell gene expression and reduced β-cell mass.
Our observations support a cell autonomous role for TCF7L2 in pancreatic β-cells suggested by most, though not all, investigations. βTCFDN is a novel model for further exploring the role of TCF7L2 in β-cell genesis and metabolic homeostasis.
在多项研究中，小鼠胰腺β细胞中TCF7L2的破坏产生了不同的结果。在此，我们旨在使用功能敲低方法阐明β细胞TCF7L2和Wnt信号传导的作用。
在Ins-1细胞中进行腺病毒介导的显性负性TCF7L2（TCF7L2DN）表达。利用由P TRE3G驱动TCF7L2DN表达的融合基因来生成转基因小鼠品系TCF7L2DN Tet。通过将TCF7L2DN Tet与Ins2-rtTA交配创建双转基因品系，命名为βTCFDN。通过喂食强力霉素在βTCFDN中诱导β细胞特异性TCF7L2DN表达。
Ins-1细胞中TCF7L2DN的表达降低了葡萄糖刺激的胰岛素分泌（GSIS）、细胞增殖以及包括肠促胰岛素受体和β细胞转录因子在内的一系列基因的表达。在成年期或断奶后立即在βTCFDN中诱导TCF7L2DN表达未产生或仅产生非常轻微的代谢缺陷，而在胚胎发育期间通过给怀孕母鼠喂食强力霉素诱导其表达则导致明显的葡萄糖不耐受，伴有β细胞基因表达改变和β细胞量减少。
我们的观察结果支持了大多数（尽管不是全部）研究所表明的TCF7L2在胰腺β细胞中的细胞自主作用。βTCFDN是进一步探索TCF7L2在β细胞发生和代谢稳态中作用的新型模型。
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