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A skin microRNA promotes differentiation by repressing ‘stemness’

Nature volume 452, pages 225–229 (2008)Cite this article

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 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.

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Figure 1: Spatiotemporal expression of miR-203 during skin development.
Figure 2: Premature activation of miR-203 in epidermis restricts its proliferative potential.
Figure 3: Inhibition of miR-203 results in increased epidermal proliferation.
Figure 4: MiR-203 targets p63 mRNA at 3′UTR.

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Acknowledgements

We thank D. O’Carroll and A. Tarakhovsky for Dicer1fl/fl mice; A. Schaefer and P. Greengard for dye-conjugated antagomir-124; Z. Zhang and F. Dietrich for miRNA library sequencing; B. Liu for bioinformatics assistance; A. Giraldez for zebrafish cDNA; N. Stokes and L. Polak for assistance with animals; S. Mazel and X. Fan for assistance in the flow cytometry core facility; J. Racelis for assistance with in situ hybridization; and D. Wang and E. Fuchs laboratory members for discussions. R.Y. is supported by the Pathway to Independence Award from the NIH. M.N.P. is supported by the Ruth L. Kirschstein NRSA Fellowship from the NIH. E.F is an investigator of the Howard Hughes Medical Institute. This work was supported by the HHMI and the NIH.

Author Contributions R.Y. and E.F. designed the research. R.Y. performed the experiments. M.N.P. and M.S. designed and contributed to the antagomir experiments. R.Y. and E.F. analysed the data and wrote the paper.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, and,,

    Rui Yi & Elaine Fuchs

  2. Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York City, New York 10065, USA,

    Rui Yi & Elaine Fuchs

  3. Swiss Federal Institute of Technology ETH Zurich, Institute of Molecular Systems Biology, CH-8093 Zürich, Switzerland

    Matthew N. Poy & Markus Stoffel

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Correspondence to Elaine Fuchs.

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M.S. is as member of the scientific advisory board of Alnylam Pharmaceuticals and Regulus Therapeutics.

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The file contains Supplementary Figures S1-S11 with Legends. The Supplementary Figures show control data and additional experimental data in support of the manuscript's conclusions. (PDF 4248 kb)

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Yi, R., Poy, M., Stoffel, M. et al. A skin microRNA promotes differentiation by repressing ‘stemness’. Nature 452, 225–229 (2008). https://doi.org/10.1038/nature06642

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