A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis

  1. Ajay Mishra
  2. Benedicte Oules
  3. Angela Oliveira Pisco
  4. Tony Ly
  5. Kifayathullah Liakath-Ali
  6. Gernot Walko
  7. Priyalakshmi Viswanathan
  8. Matthieu Tihy
  9. Jagdeesh Nijjher
  10. Sara-Jane Dunn
  11. Angus I Lamond
  12. Fiona M Watt  Is a corresponding author
  1. King's College London, United Kingdom
  2. University of Dundee, United Kingdom
  3. Microsoft Research, United Kingdom

Abstract

Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition between the two cell states, termed commitment, is poorly understood. Here we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension to induce differentiation. Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA - promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors. Conversely, DUSP10 expression antagonises commitment. The phosphatases form a dynamic network of transient positive and negative interactions that change over time, with DUSP6 predominating at commitment. Boolean network modelling identifies a mandatory switch between two stable states (stem and differentiated) via an unstable (committed) state. Phosphatase expression is also spatially regulated in vivo and in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment.

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Article and author information

Author details

  1. Ajay Mishra

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  2. Benedicte Oules

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  3. Angela Oliveira Pisco

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Tony Ly

    Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.
  5. Kifayathullah Liakath-Ali

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  6. Gernot Walko

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  7. Priyalakshmi Viswanathan

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  8. Matthieu Tihy

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9314-4657
  9. Jagdeesh Nijjher

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  10. Sara-Jane Dunn

    Microsoft Research, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  11. Angus I Lamond

    Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6204-6045
  12. Fiona M Watt

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    For correspondence
    fiona.watt@kcl.ac.uk
    Competing interests
    Fiona M Watt, Deputy editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9151-5154

Funding

Wellcome Trust (096540/Z/11/Z)

  • Benedicte Oules
  • Kifayathullah Liakath-Ali
  • Gernot Walko
  • Priyalakshmi Viswanathan
  • Jagdeesh Nijjher
  • Sara-Jane Dunn
  • Angus I Lamond
  • Fiona M Watt

Medical Research Council (G1100073)

  • Angela Oliveira Pisco

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Valerie Horsley, Yale University, United States

Publication history

  1. Received: April 1, 2017
  2. Accepted: October 10, 2017
  3. Accepted Manuscript published: October 18, 2017 (version 1)
  4. Version of Record published: November 2, 2017 (version 2)

Copyright

© 2017, Mishra et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ajay Mishra
  2. Benedicte Oules
  3. Angela Oliveira Pisco
  4. Tony Ly
  5. Kifayathullah Liakath-Ali
  6. Gernot Walko
  7. Priyalakshmi Viswanathan
  8. Matthieu Tihy
  9. Jagdeesh Nijjher
  10. Sara-Jane Dunn
  11. Angus I Lamond
  12. Fiona M Watt
(2017)
A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis
eLife 6:e27356.
https://doi.org/10.7554/eLife.27356

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