Delayed maturation of thymic epithelium in mice with specific deletion of \u03b2-catenin gene in FoxN1 positive cells

Sara Montero-Herradón,Agustín G Zapata

doi:10.1007/s00418-021-02012-w

Abstract

Wnt signalling pathways have been reported to be involved in thymus development but their precise role in the development of both thymic epithelium (TE) and thymocytes is controversial. Herein, we examined embryonic, postnatal and adult thymi of mice with a specific deletion of β-catenin gene in FoxN1+ thymic epithelial cells (TECs). Together with a high postnatal mouse mortality, the analysis showed severe thymic hypocellularity, largely due an important reduction in numbers of developing thymocytes, and delayed, partially blocked maturation of mutant TECs. Affected TECs included largely cortical (c) TEC subsets, such as immature MTS20+ TECs, Ly51+ cTECs and a remarkable, rare Ly51+MTS20+MHCIIhi cell subpopulation previously reported to contain thymic epithelial progenitor cells (TEPCs) (Ulyanchenko et al., Cell Rep 14:2819–2832, 2016). In addition, altered postnatal organization of mutant thymic medulla failed to organize a unique, central epithelial area. This delayed maturation of TE cell components correlated with low transcript production of some molecules reported to be masters for TEC maturation, such as EphB2, EphB3 and RANK. Changes in the thymic lymphoid component became particularly evident after birth, when molecules expressed by TECs and involved in early T-cell maturation, such as CCL25, CXCL12 and Dll4, exhibited minimal values. This represented a partial blockade of the progression of DN to DP cells and reduced proportions of this last thymocyte subset. At 1 month, in correlation with a significant increase in transcript production, the DP cell percentage increased in correlation with a significant fall in the number of mature TCRαβhi thymocytes and peripheral T lymphocytes.

Highlights

Wnt-mediated signals control many biological processes including cell proliferation, fate specification, cellular polarity and migration
At all the stages analysed, most total E pCAM+CD45− thymic epithelial cells (TECs) expressed β-catenin, the immature MTS20 cell population, no significant differences occurred between the proportions of β-catenin positive cells when the Ly51+UEA1− and Ly51−UEA1+ cell subsets were compared (Fig. 1b)
Our current results demonstrate that the specific deletion of β-catenin in FoxN1+ TECs corresponds to profound hypocellularity, delay and partial blockade of the maturation of thymic epithelium, largely affecting immature MTS20+ cells, presumptive bipotent Ly51+MTS20+MHCIIhi adult thymic epithelial progenitor cells (TEPCs) and cTECs

Summary

Introduction

Wnt-mediated signals control many biological processes including cell proliferation, fate specification, cellular polarity and migration (van Loosdregt et al 2013). Wnt signalling pathways comprises a canonical pathway, which is mediated by β-catenin and the transcription factor TCF (T-cell factor), and non-canonical pathways, which include the intracellular Wnt signalling and the planar polarity pathway (Korswagen 2002; Liang et al 2007). Wnt ligands (19 in humans) activate the canonical pathway by binding to surface Wnt receptors (10 of the family Frizzled -Fzd-) that form a complex with the Lrp (Low density lipoprotein receptor related protein) 5 and 6 co-receptors (Staal et al 2008). Stable β-catenin moves into the nucleus where it forms a complex with TCF/LEF-1 (Lymphoid Enhancer Factor 1) leading to activation of Wnt target genes, such as FoxN1, BclxL, Axin, cyclin D1 and c-myc (Miller 2002). Β-catenin levels directly correlate with the activity of canonical Wnt signalling (Staal and Langerak 2008; Clevers and Nusse 2012)

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