title: Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging.
abstract: 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.
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA.
authors.forename: P
authors.initials: P
authors.lastname: Burnley
authors.forename: M
authors.initials: M
authors.lastname: Rahman
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.forename: Q
authors.initials: Q
authors.lastname: Zhuge
authors.forename: D-M
authors.initials: DM
authors.lastname: Su
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013950:Thymus Gland / Q000166:cytology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C090140:Whn protein