Critical role of WNK1 in MYC-dependent early mouse thymocyte development

  1. Robert Köchl  Is a corresponding author
  2. Lesley Vanes
  3. Miriam Llorian Sopena
  4. Probir Chakravarty
  5. Harald Hartweger
  6. Kathryn Fountain
  7. Andrea White
  8. Jennifer Cowan
  9. Graham Anderson
  10. Victor LJ Tybulewicz  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. University of Birmingham, United Kingdom

Abstract

WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4+ T cells. Wnk1 is highly expressed in thymocytes, and since migration is important for thymocyte maturation, we investigated a role for WNK1 in mouse thymocyte development. We find that WNK1 is required for the transition of double negative (DN) thymocytes through the b-selection checkpoint and subsequent proliferation and differentiation into double positive (DP) thymocytes. Furthermore, we show that WNK1 negatively regulates LFA1-mediated adhesion and positively regulates CXCL12-induced migration in DN thymocytes. Despite this, migration defects of WNK1-deficient thymocytes do not account for the developmental arrest. Instead, we show that in DN thymocytes WNK1 transduces pre-TCR signals via OXSR1 and STK39 kinases and the SLC12A2 ion co-transporter that are required for post-transcriptional upregulation of MYC and subsequent proliferation and differentiation into DP thymocytes. Thus, a pathway regulating ion homeostasis is a critical regulator of thymocyte development.

Data availability

RNAseq data have been deposited in GEO under accession number GSE136210.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Robert Köchl

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    For correspondence
    Robert.Koechl@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Lesley Vanes

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Miriam Llorian Sopena

    Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Probir Chakravarty

    Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Harald Hartweger

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Kathryn Fountain

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Andrea White

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Jennifer Cowan

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Graham Anderson

    Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Victor LJ Tybulewicz

    Immune Cell Biology, The Francis Crick Institute, London, United Kingdom
    For correspondence
    Victor.T@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2439-0798

Funding

Medical Research Council (U117527252)

  • Victor LJ Tybulewicz

Francis Crick Institute (FC001194)

  • Victor LJ Tybulewicz

Medical Research Council (FC001194)

  • Victor LJ Tybulewicz

Wellcome Trust (FC001194)

  • Victor LJ Tybulewicz

Cancer Research UK (FC001194)

  • Victor LJ Tybulewicz

Biotechnology and Biological Sciences Research Council (BB/L00805X/1)

  • Victor LJ Tybulewicz

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

Ethics

Animal experimentation: All experiments were carried out under the authority of a Project Licence granted by the UK Home Office (PPL70/8843).

Reviewing Editor

  1. Bernard Malissen, Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, France

Publication history

  1. Received: March 15, 2020
  2. Accepted: October 13, 2020
  3. Accepted Manuscript published: October 14, 2020 (version 1)
  4. Version of Record published: October 27, 2020 (version 2)

Copyright

© 2020, Köchl 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. Robert Köchl
  2. Lesley Vanes
  3. Miriam Llorian Sopena
  4. Probir Chakravarty
  5. Harald Hartweger
  6. Kathryn Fountain
  7. Andrea White
  8. Jennifer Cowan
  9. Graham Anderson
  10. Victor LJ Tybulewicz
(2020)
Critical role of WNK1 in MYC-dependent early mouse thymocyte development
eLife 9:e56934.
https://doi.org/10.7554/eLife.56934

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