MicroRNA-145 Regulates Neural Stem Cell Differentiation Through the Sox2-Lin28/let-7 Signaling Pathway
MicroRNA-145 Regulates Neural Stem Cell Differentiation Through the Sox2-Lin28/let-7 Signaling Pathway
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DOI：
10.1002/stem.2309
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发表时间：
2016-05-01
期刊：
影响因子：
5.2
通讯作者：
Sola, Susana
中科院分区：
文献类型：
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作者：
Morgado, Ana L.;Rodrigues, Cecilia M. P.;Sola, Susana
MicroRNA（miRNA 或 miR）调节多种生物功能，包括细胞命运决定和分化。尽管 miR-145 已被描述可调节神经胶质瘤的发育，但其在神经发生中的确切作用从未得到解决。 miR-145 抑制性别决定区 Y-box 2 (Sox2)（胚胎干细胞 (ESC) 的核心转录因子），从而抑制人类 ESC 的多能性和自我更新。此外，Sox2-Lin28/let-7信号通路调节神经前体细胞的增殖和神经发生。在本研究中，我们旨在研究miR-145在神经干细胞（NSC）命运决定中的精确作用，以及Sox2-Lin28/let-7信号通路在miR-145调控网络中的可能参与。我们的结果首次表明，在诱导小鼠 NSC 分化后，miR-145 表达显着增加，并在整个过程中保持升高状态。强制 miR-145 下调会降低神经元标志物，即 β III-微管蛋白、NeuN 和 MAP2。有趣的是，在 NSC 分化过程中，Sox2 和 Lin28（众所周知的 let-7 生物合成抑制因子）的蛋白质水平下降。值得注意的是，神经元分化也导致 let-7a 和 let-7b 上调。用抗 miR-145 转染 NSC 反过来又增加了 Sox2 和 Lin28 蛋白水平，同时降低了 let-7a 和 let-7b。更重要的是，Sox2 和 Lin28 沉默部分挽救了 miR-145 下调引起的神经元分化损伤。总之，我们的结果证明了 miR-145 在 NSC 分化过程中的新作用，其中 miR-145 对 Sox2-Lin28/let-7 网络的调节对于神经发生进展至关重要。
MicroRNAs (miRNAs or miRs) regulate several biological functions, including cell fate determination and differentiation. Although miR-145 has already been described to regulate glioma development, its precise role in neurogenesis has never been addressed. miR-145 represses sex-determining region Y-box 2 (Sox2), a core transcription factor of embryonic stem cells (ESCs), to inhibit pluripotency and self-renewal in human ESCs. In addition, the Sox2-Lin28/let-7 signaling pathway regulates proliferation and neurogenesis of neural precursors. In this study, we aimed to investigate the precise role of miR-145 in neural stem cell (NSC) fate decision, and the possible involvement of the Sox2-Lin28/let-7 signaling pathway in miR-145 regulatory network. Our results show for the first time that miR-145 expression significantly increased after induction of mouse NSC differentiation, remaining elevated throughout this process. Forced miR-145 downregulation decreased neuronal markers, namely beta III-tubulin, NeuN, and MAP2. Interestingly, throughout NSC differentiation, protein levels of Sox2 and Lin28, a well-known suppressor of let-7 biogenesis, decreased. Of note, neuronal differentiation also resulted in let-7a and let-7b upregulation. Transfection of NSCs with anti-miR-145, in turn, increased both Sox2 and Lin28 protein levels, while decreasing both let-7a and let-7b. More importantly, Sox2 and Lin28 silencing partially rescued the impairment of neuronal differentiation induced by miR-145 downregulation. In conclusion, our results demonstrate a novel role for miR-145 during NSC differentiation, where miR-145 modulation of Sox2-Lin28/let-7 network is crucial for neurogenesis progression.