ROLE OF THE P63-FOXN1 REGULATORY AXIS IN THYMIC EPITHELIAL CELL HOMEOSTASIS DURING AGING

Purpose: Current knowledge about regulating proliferation and differentiation of thymic epithelial cells (TECs) by the genes p63 and FoxN1, respectively, in the prenatal thymus has led our lab to determine whether these genes also regulate TEC homeostasis during aging in the postnatal thymus. Methods: We used murine models to verify the role of a p63-FoxN1 regulatory axis in TEC homeostasis during thymic aging. Results: Our studies show that a proportion of pan-p63+ TECs was increased with age, among which the isoform, TAp63, as oppose to ΔNp63, was increased and accompanied by increased senescent cell clusters with age. Furthermore, in the postnatal thymus blockade of the TEC differentiation via a conditional FoxN1 knockout demonstrated an increase in TAp63 and senescent cell clusters as well. This proportion of TAp63+ TECs, however, was decreased when FoxN1 cDNA was exogenously administered into the aged thymus intrathymically. In addition, we found that increased TAp63+ populations contained high proportions of phosphorylated-p53+ and apoptotic TECs but showed no changes in BrdU-labeled proliferation. Lastly, TAp63 cDNA intrathymically injected into the young thymus showed an increase in senescent cell clusters but little change in FoxN1. Conclusions: We conclude that the expression of TAp63 has a reverse correlation with expression of FoxN1. During the natural thymic aging, decrease in FoxN1 causes an accumulation of undifferentiated TECs. This most likely leads to an increase in TAp63, thus resulting in an increase in cellular senescence and exhaustion of epithelial stem cells. This finally will cause age-related thymic involution and deteriorate thymic function.