Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
PLoS One. 2011;6(8):e21396. doi: 10.1371/journal.pone.0021396. Epub 2011 Aug 3.
MicroRNAs (miRNAs or miRs) participate in the regulation of several biological processes, including cell differentiation. Recently, miR-34a has been implicated in the differentiation of monocyte-derived dendritic cells, human erythroleukemia cells, and mouse embryonic stem cells. In addition, members of the miR-34 family have been identified as direct p53 targets. However, the function of miR-34a in the control of the differentiation program of specific neural cell types remains largely unknown. Here, we investigated the role of miR-34a in regulating mouse neural stem (NS) cell differentiation.
METHODOLOGY/PRINCIPAL FINDINGS: miR-34a overexpression increased postmitotic neurons and neurite elongation of mouse NS cells, whereas anti-miR-34a had the opposite effect. SIRT1 was identified as a target of miR-34a, which may mediate the effect of miR-34a on neurite elongation. In addition, acetylation of p53 (Lys 379) and p53-DNA binding activity were increased and cell death unchanged after miR-34a overexpression, thus reinforcing the role of p53 during neural differentiation. Interestingly, in conditions where SIRT1 was activated by pharmacologic treatment with resveratrol, miR-34a promoted astrocytic differentiation, through a SIRT1-independent mechanism.
Our results provide new insight into the molecular mechanisms by which miR-34a modulates neural differentiation, suggesting that miR-34a is required for proper neuronal differentiation, in part, by targeting SIRT1 and modulating p53 activity.
MicroRNAs（miRNAs 或 miRs）参与多个生物学过程的调节，包括细胞分化。最近，miR-34a 已被牵涉到单核细胞衍生的树突状细胞、人红白血病细胞和小鼠胚胎干细胞的分化中。此外，miR-34 家族的成员已被鉴定为直接的 p53 靶标。然而，miR-34a 在控制特定神经细胞类型的分化程序中的功能在很大程度上仍然未知。在这里，我们研究了 miR-34a 在调控小鼠神经干细胞（NS）细胞分化中的作用。
方法/主要发现：miR-34a 的过表达增加了小鼠 NS 细胞的有丝分裂后神经元和神经突的伸长，而抗-miR-34a 则有相反的效果。SIRT1 被鉴定为 miR-34a 的靶标，它可能介导 miR-34a 对神经突伸长的影响。此外，乙酰化的 p53（Lys 379）和 p53-DNA 结合活性增加，细胞死亡在 miR-34a 过表达后不变，从而在神经分化过程中增强了 p53 的作用。有趣的是，在使用白藜芦醇进行药物治疗激活 SIRT1 的情况下，miR-34a 通过一种不依赖于 SIRT1 的机制促进星形胶质细胞分化。
我们的结果为 miR-34a 调节神经分化的分子机制提供了新的见解，表明 miR-34a 通过靶向 SIRT1 和调节 p53 活性，是适当的神经元分化所必需的。
