Reciprocal Regulation between Bifunctional miR-9/9∗ and its Transcriptional Modulator Notch in Human Neural Stem Cell Self-Renewal and Differentiation

•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

SummaryTight 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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