Critical role of WNK1 in MYC-dependent early mouse thymocyte development
- The Francis Crick Institute, United Kingdom
- 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.
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Analysis of anti-CD3e-induced transcriptional changes in WNK1-deficient thymocytesNCBI Gene Expression Omnibus, GSE136210.
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Expression and regulation of lincRNAs during T cell development and differentiationNCBI Gene Expression Omnibus, GSENCBI Gene Expression Omnibus, GSE48138.
Article and author information
Author details
Victor LJ Tybulewicz
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).
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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Critical role of WNK1 in MYC-dependent early mouse thymocyte development
eLife 9:e56934.
https://doi.org/10.7554/eLife.56934
