Stem Cell Reports
Volume 7, Issue 2, 9 August 2016, Pages 207-219
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Article
Reciprocal Regulation between Bifunctional miR-9/9 and its Transcriptional Modulator Notch in Human Neural Stem Cell Self-Renewal and Differentiation

https://doi.org/10.1016/j.stemcr.2016.06.008Get rights and content
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Highlights

  • MiR-9/9 regulate Notch signaling by targeting NOTCH2 and HES1

  • Notch directly regulates transcription of the miR-9_2 genomic locus

  • Notch-miR-9 reciprocal regulation calibrates NSC self-renewal and differentiation

Summary

Tight regulation of the balance between self-renewal and differentiation of neural stem cells is crucial to assure proper neural development. In this context, Notch signaling is a well-known promoter of stemness. In contrast, the bifunctional brain-enriched microRNA miR-9/9 has been implicated in promoting neuronal differentiation. Therefore, we set out to explore the role of both regulators in human neural stem cells. We found that miR-9/9 decreases Notch activity by targeting NOTCH2 and HES1, resulting in an enhanced differentiation. Vice versa, expression levels of miR-9/9 depend on the activation status of Notch signaling. While Notch inhibits differentiation of neural stem cells, it also induces miR-9/9 via recruitment of the Notch intracellular domain (NICD)/RBPj transcriptional complex to the miR-9/9_2 genomic locus. Thus, our data reveal a mutual interaction between bifunctional miR-9/9 and the Notch signaling cascade, calibrating the delicate balance between self-renewal and differentiation of human neural stem cells.

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