Journal
STEM CELL REPORTS
Volume 9, Issue 6, Pages 1991-2004Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2017.10.030
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Funding
- European Union [618432-MC-Epi-Patho-Stem]
- Israel Science Foundation
- TECHNION V.P.R FUND- MALLAT FAMILY RESEARCH FUND
- Rappaport family fund
- French Agence Nationale pour la Recherche [ANR-11-EMMA-023]
- Fondation pour la Recherche Medicale (FRM team)
- Israel Ministry of Science and Technology (MOST) [2015483]
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miR-184 is a highly evolutionary conserved microRNA (miRNA) from fly to human. The importance of miR-184 was underscored by the discovery that point mutations in miR-184 gene led to corneal/lens blinding disease. However, miR-184-related function in vivo remained unclear. Here, we report that the miR-184 knockout mouse model displayed increased p63 expression in line with epidermal hyperplasia, while forced expression of miR-184 by stem/progenitor cells enhanced the Notch pathway and induced epidermal hypoplasia. In line, miR-184 reduced clonogenicity and accelerated differentiation of human epidermal cells. We showed that by directly repressing cytokeratin 15 (K15) and FIH1, miR-184 induces Notch activation and epidermal differentiation. The disease-causing miR-184(C57U) mutant failed to repress K15 and FIH1 and to induce Notch activation, suggesting a loss-of-function mechanism. Altogether, we propose that, by targeting K15 and FIH1, miR-184 regulates the transition from proliferation to early differentiation, while mis-expression or mutation in miR-184 results in impaired homeostasis.
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