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MicroRNA-205 controls neonatal expansion of skin stem cells by modulating the PI(3)K pathway

Nature Cell Biology volume 15, pages 11531163 (2013) | Download Citation

Abstract

Skin stem cells (SCs) are specified and rapidly expanded to fuel body growth during early development. However, the molecular mechanisms that govern the amplification of skin SCs remain unclear. Here we report an essential role for miR-205, one of the most highly expressed microRNAs in skin SCs, in promoting neonatal expansion of these cells. Unlike most mammalian miRNAs, genetic deletion of miR-205 causes neonatal lethality with severely compromised epidermal and hair follicle growth. In the miR-205 knockout skin SCs, phospho-Akt is significantly downregulated, and the SCs prematurely exit the cell cycle. In the hair follicle, this accelerates the transition of the neonatal SCs towards quiescence. We identify multiple miR-205-targeted negative regulators of PI(3)K signalling that mediate the repression of phospho-Akt and restrict the proliferation of SCs. Our findings reveal an essential role for miR-205 in maintaining the expansion of skin SCs by antagonizing negative regulators of PI(3)K signalling.

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Acknowledgements

We are grateful to E. Fuchs for K14–RFP mice. We thank T. Blumenthal, T. Cech, B. Cullen, M. Han, M. Winey and X-J. Wang for comments on the manuscript. We thank C. Yang, J. Gao and D. Feng for the generation of miR-205 KO; S. Ha and L. Greiner for assistance in the animal facility; Y. Han for FACS; and G. Voeltz for confocal microscopy. We also thank members of the Yi laboratory for their critical discussions. This publication was made possible by a start-up fund provided by the University of Colorado and Grant Number R00AR054704 and R01AR059697 (R.Y.) and R01GM083300 (E.C.L.).

Author information

Author notes

    • Zhaojie Zhang
    •  & Evan O’Loughlin

    These authors contributed equally to this work

    • Evan O’Loughlin

    Present address: Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115, USA

Affiliations

  1. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA

    • Dongmei Wang
    • , Zhaojie Zhang
    • , Evan O’Loughlin
    • , Li Wang
    • , Xiying Fan
    •  & Rui Yi
  2. Sloan-Kettering Institute, 1017 Rockefeller Research Labs, 1275 York Avenue Box 252, New York, New York 10065, USA

    • Eric C. Lai

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Contributions

R.Y. conceived the study. D.W. carried out most experiments and analysed the data with assistance from Z.Z. (bioinformatic analysis), E.O. (in situ hybridization), L.W. (ChIP-seq and RNA-seq) and X.F. (target validation). E.C.L. provided critical resources. R.Y. and D.W. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rui Yi.

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https://doi.org/10.1038/ncb2827

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