1. Howard Hughes Medical Institute, and,
2. Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York City, New York 10065, USA
3. Swiss Federal Institute of Technology ETH Zurich, Institute of Molecular Systems Biology, CH-8093 Zürich, Switzerland

Correspondence to: Elaine Fuchs^1,2 Correspondence and requests for materials should be addressed to E.F. (Email: fuchslb@rockefeller.edu).

Abstract

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 programme^{2, 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 tissues^{4, 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.

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