Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
Immunol Cell Biol. 2013 Sep;91(8):511-23. doi: 10.1038/icb.2013.34. Epub 2013 Jul 16.
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.
β-连环蛋白在胸腺细胞发育中的作用已得到广泛研究，然而，β-连环蛋白在胸腺上皮细胞（TEC）中的功能仍很大程度上不清楚。在这里，我们证明了β-连环蛋白在角蛋白 5（K5）表达的 TEC 中的必要性，这些 TEC 构成了成年早期胸腺中大多数髓质 TEC（mTEC）和皮质 TEC（cTEC）的前体细胞。我们发现，条件性敲除 K5(+)-TEC 及其祖细胞中的β-连环蛋白导致胸腺萎缩。TEC 的组成也受到异常影响。与对照胸腺相比，K5(hi)K8(+)-TEC、K5(+)K8(-)-TEC 和 UEA1(+)-mTEC 的百分比显著降低，K5(lo)K8(+)-TEC 和 Ly51(+)-cTEC 的百分比增加。我们还观察到，使用谱系追踪方法，β-连环蛋白缺陷的 TEC 谱系能够比野生型 TEC 更有效地产生 K8(+)-cTEC。重要的是，β-连环蛋白缺陷胸腺中的几个转录因子（p63、FoxN1 和 Aire）的表达水平发生了改变，这些转录因子对于 TEC 分化是必需的。在 TEC 异常分化的情况下，β-连环蛋白缺陷胸腺中的所有胸腺细胞的发育都受到了损害。白细胞介素 7（IL-7）和趋化因子（Ccl19、Ccl25 和 Cxcl12）的水平在突变体中的胸腺基质细胞中也下调。最后，在淋巴细胞谱系中引入 BCL2 转基因，已被证明可以挽救 IL-7 缺陷的胸腺生成，部分挽救了 K5(+)-TEC 中诱导的β-连环蛋白缺失引起的胸腺萎缩和胸腺细胞发育缺陷。总之，这些发现表明β-连环蛋白是 TEC 分化所必需的，从而有助于出生后胸腺中的胸腺细胞发育。
