Abstract
SummarymiR-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.
Highlights
The skin and cornea serve as a barrier that is protecting our body against exterior insults
Similar to the interfollicular epidermis (IFE), hair-follicle stem cells (SCs) (HFSCs) and limbal SCs (LSCs) that regenerate the corneal epithelium are located in discrete niches and engage similar differentiation programs (Amitai-Lange et al, 2015; Cotsarelis et al, 1989, 1990; Di Girolamo et al, 2015)
Low or no signal was found in the epidermal basal layer cells at E18.5 and postnatal day 8 (P8) (Figure 1B, high magnification, white arrow)
Summary
The skin and cornea serve as a barrier that is protecting our body against exterior insults. The classical dogma describes epidermal SCs as slowcycling cells that are rare in the niche, surrounded by ten fast-dividing but short-lived progenitor cells (Mascre et al, 2012; Potten et al, 1974) This deterministic paradigm can explain the heterogeneity of basal epidermal cells in vivo and ex vivo; against this dogma, there are no specific markers that label slow-cycling SCs. An alternative stochastic model suggests that the entire basal layer is occupied by equipotent fast-dividing progenitor cells that compete for niche factors for survival (Clayton et al, 2007; Rompolas et al, 2016; Bacman et al, 2013). In light of this controversy, it would be important to clarify the mechanisms of SC regulation and the sharp switch from proliferative to post-mitotic compartment, which is only partially understood
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