A skin microRNA promotes differentiation by repressing ‘stemness’

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Abstract
Epithelial tissues such as the skin are able to self-renew, thanks to the stem cells located in a basal layer. Cells originating from these stem cells differentiate — losing the ability to proliferate — as they grow towards the tissue surface. Now a microRNA has been linked to this process of stratification and differentiation. miR-203 is not expressed in epidermal stem cells, but it is made as cells commit to differentiate. It represses the cell's 'stemness' and enforces differentiation by suppressing the production of p63, a protein that is known to regulate stem cell maintenance in skin. A microRNA (miR-203) that promotes differentiation of stratified epithelial stem cells by restricting their proliferation and inducing cell cycle exit is identified. One of its targets is p63, which regulates stem cells maintenance in skin, and it is shown that miR2-3 works by repressing p63 expression. In stratified epithelial tissues, homeostasis relies on the self-renewing capacity of stem cells located within the innermost basal layer1. As basal cells become suprabasal, they lose proliferative potential and embark on a terminal differentiation programme2,3. Here, we show that microRNA-203 is induced in the skin concomitantly with stratification and differentiation. By altering miR-203’s spatiotemporal expression in vivo, we show that miR-203 promotes epidermal differentiation by restricting proliferative potential and inducing cell-cycle exit. We identify p63 as one of the conserved targets of miR-203 across vertebrates. Notably, p63 is an essential regulator of stem-cell maintenance in stratified epithelial tissues4,5,6,7,8,9. We show that miR-203 directly represses the expression of p63: it fails to switch off suprabasally when either Dicer1 or miR-203 is absent and it becomes repressed basally when miR-203 is prematurely expressed. Our findings suggest that miR-203 defines a molecular boundary between proliferative basal progenitors and terminally differentiating suprabasal cells, ensuring proper identity of neighbouring layers.