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Stem Cell Reports. 2016 Aug 9;7(2):207-19. doi: 10.1016/j.stemcr.2016.06.008. Epub 2016 Jul 14.

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

Author information

1
Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn, 53127 Bonn, Germany.
2
Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn, 53127 Bonn, Germany; DZNE, German Center for Neurodegenerative Diseases, 53127 Bonn, Germany.
3
Department of Neurology, University of Bonn, 53127 Bonn, Germany.
4
Institute of Reconstructive Neurobiology, LIFE & BRAIN Center, University of Bonn, 53127 Bonn, Germany; DZNE, German Center for Neurodegenerative Diseases, 53127 Bonn, Germany. Electronic address: brustle@uni-bonn.de.

Abstract

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.

PMID:
27426040
PMCID:
PMC4982985
DOI:
10.1016/j.stemcr.2016.06.008
[Indexed for MEDLINE]
Free PMC Article

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