Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.
J Neurochem. 2013 Sep;126(6):771-80. doi: 10.1111/jnc.12370. Epub 2013 Aug 6.
microRNAs are a class of small non-coding RNA molecules negatively regulating gene expression at post-transcriptional level in many tissues including the central nervous system. cAMP response element binding protein (CREB) is a key nuclear factor highly expressed in hippocampal neurons on which many signal pathways converge. Recent studies have found that microRNA-181a is rich in mature nerve cells, and bioinformatics analysis shows that the CREB1 mRNA 3'-untranslated region (3'UTR) contains complementary sequence to the miR-181a seed region. In this study, we investigated whether miR-181a is a negative regulator for CREB1 expression in neurons. It was found that the expression of miR-181a was negatively correlated with Insulin-like growth factor-1 (IGF-1) and CREB1 in the Lewis rat hippocampus. miR-181a bound to CREB1 mRNA through a specific binding site in the 3'UTR sequence. The expression of CREB1 in PC12 cells was down-regulated by transfection with a miR-181a mimic and up-regulated by a miR-181a inhibitor. A down-regulated miR-181a and an up-regulated CREB1 were observed in IGF-1-stimulated PC12 cells. And miR-181a inhibited dendritic growth of cultured hippocampus neurons. These suggest that miR-181a is involved in IGF-1-regulated CREB1 expression by targeting its mRNA 3'UTR. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and are involved in the central nervous system development. Here, we demonstrate that miR-181a can inhibit the expression of the transcription factor CREB1 by specifically targeting its mRNA 3'UTR and inhibit the development of hippocampus neurons. Repressed expression of miR-181a is involved in IGF-1-mediated up-regulation of CREB1 in vivo and in vitro. These findings indicate that miR-181a could be a potential target for preventing neurodegenerative diseases.
microRNAs 是一类小的非编码 RNA 分子，在包括中枢神经系统在内的许多组织中，通过转录后水平负调控基因表达。cAMP 反应元件结合蛋白（CREB）是一种在海马神经元中高度表达的关键核因子，许多信号途径都集中于此。最近的研究发现，microRNA-181a 在成熟的神经细胞中含量丰富，生物信息学分析表明，CREB1 mRNA 的 3'非翻译区（3'UTR）含有与 miR-181a 种子区互补的序列。在本研究中，我们研究了 miR-181a 是否是神经元中 CREB1 表达的负调节剂。结果发现，Lewis 大鼠海马中 miR-181a 的表达与胰岛素样生长因子-1（IGF-1）和 CREB1 呈负相关。miR-181a 通过 3'UTR 序列中的特定结合位点与 CREB1 mRNA 结合。用 miR-181a 模拟物转染 PC12 细胞可下调 CREB1 的表达，而用 miR-181a 抑制剂转染则可上调 CREB1 的表达。在 IGF-1 刺激的 PC12 细胞中观察到 miR-181a 下调和 CREB1 上调。并且 miR-181a 抑制培养的海马神经元的树突生长。这些结果表明，miR-181a 通过靶向其 mRNA 3'UTR 参与 IGF-1 调节的 CREB1 表达。microRNAs（miRNAs）通过在转录后水平调控基因表达，参与中枢神经系统的发育。在这里，我们证明 miR-181a 可以通过特异性靶向其 mRNA 3'UTR 来抑制转录因子 CREB1 的表达，并抑制海马神经元的发育。miR-181a 的表达受抑制与体内和体外 IGF-1 介导的 CREB1 上调有关。这些发现表明，miR-181a 可能是预防神经退行性疾病的潜在靶点。
