microRNA-184 Induces a Commitment Switch to Epidermal Differentiation

Abstract

Summary: 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-184C57U 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. : Using new genetic mouse models and study of human epidermal cells, Nagosa et al. show that miR-184 regulates epidermal proliferation and commitment to differentiation. The authors discovered that miR-184 directly represses K15 and FIH1, which are important for the maintenance of stemness phenotype. Keywords: microRNA, miR-184, miRNA-184, K15, FIH1, notch, stem cells, epidermis, hair follicle, cornea