The miR-17/106–p38 axis is a key regulator of the neurogenic-to-gliogenic transition in developing neural stem/progenitor cells

Significance Neural stem/progenitor cells (NSPCs) restrict their differentiation potential by developmental stage-dependent temporal specification. Thereby, specific and efficient induction of homogeneous target cell populations remains a challenge in stem cell biology. Here, we provided a potential solution by identifying the molecular machinery responsible for neurogenic-to-gliogenic transition of NSPCs, a process we termed “competence change.” We identified the microRNA-17/106–p38 axis as a critical regulator of the competence change, although epigenetic regulation seemed to be the regulatory program behind it, by our previous Coup-tf study. NSPCs sustained and restored neurogenic potential by competence regulation. Moreover, at least a part of neuron-subtype specification was regulated independent of it. Control of these multilayered regulatory programs seems promising for rigorous manipulation of cytogenesis from NSPCs. 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.

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