The miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic transition in developing neural stem/progenitor cells
The miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic transition in developing neural stem/progenitor cells
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DOI：
10.1073/pnas.1315567111
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发表时间：
2014-01-28
影响因子：
11.1
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
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作者：
Naka-Kaneda, Hayato;Nakamura, Shiho;Okano, Hideyuki
神经干/祖细胞（NSPC）的多能性受到高度调节，从而在发育过程中形成特定的神经网络。NSPCs不能响应胶质信号而不获得胶质生成能力，并随着发育的进行而降低其神经生成能力。Coup-tfI和Coup-tfII是这些时间NSPC能力变化的触发器。然而，下游效应的Coup-tfs介导的神经原性胶质细胞生成能力的转变仍然是未知的。在这里，我们确定了microRNA-17/106（miR-17/106）-p38轴作为这种转变的关键调节因子。miR-17的过表达抑制了胶质细胞生成能力的获得，并迫使阶段进展的NSPCs在不改变胶质细胞基因启动子甲基化状态的情况下恢复神经原性能力。我们还确定了Mapk 14（也称为p38）作为miR-17/106的靶点，并发现Mapk 14抑制在神经发生期后恢复了神经发生能力。这些结果表明，miR-17/106-p38轴是神经源性到胶质源性NSPC能力转变的关键调节因子，并且操纵该轴允许双向控制NSPC多能性。
Neural stem/progenitor cell (NSPC) multipotency is highly regulated so that specific neural networks form during development. NSPCs cannot respond to gliogenic signals without acquiring gliogenic competence and decreasing their neurogenic competence as development proceeds. Coup-tfI and Coup-tfII are triggers of these temporal NSPC competence changes. However, the downstream effectors of Coup-tfs that mediate the neurogenic-to-gliogenic competence transition remain unknown. Here, we identified the microRNA-17/106 (miR-17/106)-p38 axis as a critical regulator of this transition. Overexpression of miR-17 inhibited the acquisition of gliogenic competence and forced stage-progressed NSPCs to regain neurogenic competence without altering the methylation status of a glial gene promoter. We also identified Mapk14 (also known as p38) as a target of miR-17/106 and found that Mapk14 inhibition restored neurogenic competence after the neurogenic phase. These results demonstrate that the miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic NSPC competence transition and that manipulation of this axis permits bidirectional control of NSPC multipotency.