title: Thymic epithelial β-catenin is required for adult thymic homeostasis and function.
abstract: The role of β-catenin in thymocyte development has been extensively studied, however, the function of β-catenin in thymic epithelial cells (TECs) remains largely unclear. Here, we demonstrate a requirement for β-catenin in keratin 5 (K5)-expressing TECs, which comprise the majority of medullary TECs (mTECs) and a progenitor subset for cortical TECs (cTECs) in the young adult thymus. We found that conditionally ablated β-catenin in K5(+)-TECs and their progeny cells resulted in thymic atrophy. The composition of TECs was also aberrantly affected. Percentages of K5(hi)K8(+)-TECs, K5(+)K8(-)-TECs and UEA1(+)-mTECs were significantly decreased and the percentage of K5(lo)K8(+)-TECs and Ly51(+)-cTECs were increased in β-catenin-deficient thymi compared with that in the control thymi. We also observed that β-catenin-deficient TEC lineage could give rise to K8(+)-cTECs more efficiently than wild-type TECs using lineage-tracing approach. Importantly, the expression levels of several transcription factors (p63, FoxN1 and Aire), which are essential for TEC differentiation, were altered in β-catenin-deficient thymi. Under the aberrant differentiation of TECs, development of all thymocytes in β-catenin-deficient thymi was impaired. Interleukin-7 (IL-7) and chemokines (Ccl19, Ccl25 and Cxcl12) levels were also downregulated in the thymic stromal cells in the mutants. Finally, introducing a BCL2 transgene in lymphoid lineages, which has been shown to rescue IL-7-deficient thymopoiesis, partially rescued the thymic atrophy and thymocyte development defects caused by induced ablation of β-catenin in K5(+)-TECs. Collectively, these findings suggest that β-catenin is required for the differentiation of TECs, thereby contributing to thymocyte development in the postnatal thymus.
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chih-Chia
authors.initials: CC
authors.lastname: Liang
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: You
authors.forename: Jeffrey J Y
authors.initials: JJ
authors.lastname: Yen
authors.forename: Nan-Shih
authors.initials: NS
authors.lastname: Liao
authors.forename: Hsin-Fang
authors.initials: HF
authors.lastname: Yang-Yen
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Chen
mesh_terms: D000818:Animals; D001284:Atrophy / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004848:Epithelium / Q000276:immunology / Q000378:metabolism*; D019254:Genes, bcl-2 / Q000235:genetics; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology*; D013950:Thymus Gland / Q000254:growth & development / Q000473:pathology*; D014158:Transcription, Genetic / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D053555:Keratin-5; D051176:beta Catenin