Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging.
Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging.
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DOI：
10.1038/cddis.2013.460
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发表时间：
2013-11-21
影响因子：
9
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中科院分区：
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p63 基因调节胸腺上皮细胞 (TEC) 增殖，而 FoxN1 调节其分化。然而，它们在胸腺衰老过程中 TEC 稳态调节中的协同作用尚不清楚。在小鼠模型中，TAp63+（而非 ΔNp63+）TEC 的比例随着年龄的增长而增加，这与衰老细胞簇（以 SA-β-Gal+ 和 p21+ 细胞为特征）的年龄相关增加有关。将外源 TAp63 cDNA 胸腺内输注到年轻的野生型 (WT) 小鼠中会导致衰老细胞簇的增加。通过条件性 FoxN1 基因敲除来阻断 TEC 分化，加速了这种表型在中年早期的出现，而将外源性 FoxN1 cDNA 注入老年 WT 小鼠胸腺内仅导致 TAp63+ TEC 比例适度减少，但部分恢复活力的胸腺中 ΔNp63+ TEC 有所增加。同时，我们发现增加的TAp63+群体含有高比例的磷酸化p53 TEC，这可能参与诱导细胞衰老。因此，TAp63 水平与 TEC 衰老呈正相关，但与 FoxN1 的表达和 FoxN1 调节的 TEC 分化呈负相关。由此，揭示了 p63-FoxN1 调节轴在调节出生后 TEC 稳态中的作用。
The p63 gene regulates thymic epithelial cell (TEC) proliferation, whereas FoxN1 regulates their differentiation. However, their collaborative role in the regulation of TEC homeostasis during thymic aging is largely unknown. In murine models, the proportion of TAp63+, but not ΔNp63+, TECs was increased with age, which was associated with an age-related increase in senescent cell clusters, characterized by SA-β-Gal+ and p21+ cells. Intrathymic infusion of exogenous TAp63 cDNA into young wild-type (WT) mice led to an increase in senescent cell clusters. Blockade of TEC differentiation via conditional FoxN1 gene knockout accelerated the appearance of this phenotype to early middle age, whereas intrathymic infusion of exogenous FoxN1 cDNA into aged WT mice brought only a modest reduction in the proportion of TAp63+ TECs, but an increase in ΔNp63+ TECs in the partially rejuvenated thymus. Meanwhile, we found that the increased TAp63+ population contained a high proportion of phosphorylated-p53 TECs, which may be involved in the induction of cellular senescence. Thus, TAp63 levels are positively correlated with TEC senescence but inversely correlated with expression of FoxN1 and FoxN1-regulated TEC differentiation. Thereby, the p63-FoxN1 regulatory axis in regulation of postnatal TEC homeostasis has been revealed.