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

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.