Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging

Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA.
Cell Death & Disease (Impact Factor: 5.01). 11/2013; 4(11):e932. DOI: 10.1038/cddis.2013.460
Source: PubMed


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.

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Available from: Preston Burnley, Mar 04, 2014
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    • "This age-associated reduction in immature Meis1high cells potentially containing postnatal TEC progenitors seems to be one of the potential mechanisms involved in age-associated thymic involution. In this regard, p63, in association with FoxN1, has also recently been revealed to participate in age-related thymic involution [48]. Further studies on the function of Meis1 in TECs, in relation to the p63-FoxN1 regulatory axis, could provide an avenue for clarifying the molecular mechanism underlying age-associated thymic atrophy. "
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