MicroRNA-122 regulates polyploidization in the murine liver.
MicroRNA-122 regulates polyploidization in the murine liver.
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DOI：
10.1002/hep.28573
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
Duncan AW
中科院分区：
文献类型：
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作者：
Hsu SH;Delgado ER;Otero PA;Teng KY;Kutay H;Meehan KM;Moroney JB;Monga JK;Hand NJ;Friedman JR;Ghoshal K;Duncan AW
哺乳动物肝脏的一个决定性特征是多倍体，即整个染色体补体的数值变化。多倍体化的第一步包括细胞分裂失败。虽然多倍体很常见，影响约90%的小鼠肝细胞和50%的人类肝细胞，但多倍体细胞在肝脏稳态和疾病中所起的特殊作用仍然知之甚少。本研究的目的是确定调节多倍体的新信号，我们关注的是microRNAs （miRNAs）。首先，为了测试mirna是否可以调节肝脏多倍体，我们检查了缺乏成熟mirna的Dicer1肝脏特异性敲除小鼠的肝脏。mirna的缺失导致双核肝细胞减少3倍，表明mirna调节多倍体化。其次，我们调查了野生型小鼠中mirna的年龄依赖性表达，并确定了包括miR-122在内的mirna子集在2-3周（广泛多倍体发生的时期）差异表达。接下来，我们检测了Mir122敲除小鼠，观察到多倍体肝细胞的严重、终身耗竭，证明miR-122是肝脏完全多倍体化所必需的。此外，miR-122敲除小鼠的多倍体缺陷通过腺病毒介导的miR-122过表达得到改善，强调了miR-122在多倍体化中的关键作用。最后，我们确定了miR-122调节细胞分裂的直接靶点（Cux1, Rhoa, Iqgap1, Mapre1， Nedd4l和Slc25a34）。抑制每个靶点诱导细胞分裂失败并促进肝双核。我们的数据表明miR-122在肝脏多倍体化中是必要的和充分的。在与肝脏多倍体相关的不同信号中，miR-122是第一个被发现的肝脏特异性信号。这些研究将为未来研究miR-122在肝脏成熟、体内平衡和疾病中的作用奠定基础。
A defining feature of the mammalian liver is polyploidy, a numerical change in the entire complement of chromosomes. The first step of polyploidization involves cell division with failed cytokinesis. Although polyploidy is common, affecting ~90% of hepatocytes in mice and 50% in humans, the specialized role played by polyploid cells in liver homeostasis and disease remains poorly understood. The goal of this study was to identify novel signals that regulate polyploidization, and we focused on microRNAs (miRNAs). First, to test whether miRNAs could regulate hepatic polyploidy we examined livers from Dicer1 liver-specific knockout mice, which are devoid of mature miRNAs. Loss of miRNAs resulted in a 3-fold reduction in binucleate hepatocytes, indicating that miRNAs regulate polyploidization. Secondly, we surveyed age-dependent expression of miRNAs in wild-type mice and identified a subset of miRNAs, including miR-122, that is differentially expressed at 2–3 weeks, a period when extensive polyploidization occurs. Next, we examined Mir122 knockout mice and observed profound, life-long depletion of polyploid hepatocytes, proving that miR-122 is required for complete hepatic polyploidization. Moreover, the polyploidy defect in Mir122 knockout mice was ameliorated by adenovirus-mediated over-expression of miR-122, underscoring the critical role miR-122 plays in polyploidization. Finally, we identified direct targets of miR-122 (Cux1, Rhoa, Iqgap1, Mapre1, Nedd4l and Slc25a34) that regulate cytokinesis. Inhibition of each target induced cytokinesis failure and promoted hepatic binucleation. Our data demonstrate that miR-122 is both necessary and sufficient in liver polyploidization. Among the different signals that have been associated with hepatic polyploidy, miR-122 is the first liver-specific signal identified. These studies will serve as the foundation for future work investigating miR-122 in liver maturation, homeostasis and disease.