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

• Published in: eLife Vol. 9
• Main Authors: Köchl, Robert, Vanes, Lesley, Llorian Sopena, Miriam, Chakravarty, Probir, Hartweger, Harald, Fountain, Kathryn, White, Andrea, Cowan, Jennifer, Anderson, Graham, Tybulewicz, Victor Lj
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 14.10.2020; eLife Sciences Publications, Ltd; eLife Sciences Publications Ltd
• Subjects: Animals; Cell Differentiation - genetics; CXCR4; Immunology and Inflammation; Mice; MYC; pre-TCR; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; signal transduction; T cells; thymocytes; Thymocytes - metabolism; Thymus Gland - metabolism; WNK Lysine-Deficient Protein Kinase 1 - genetics; WNK Lysine-Deficient Protein Kinase 1 - metabolism; WNK1; mouse; WNK1; inflammation; signal transduction; MYC; CXCR4; thymocytes; immunology; pre-TCR
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.56934

WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4 T cells. 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 β-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.