TY - JOUR
T1 - Role of the p63-FoxN1 regulatory axis in thymic epithelial cell homeostasis during aging
AU - Burnley, P.
AU - Rahman, M.
AU - Wang, H.
AU - Zhang, Z.
AU - Sun, X.
AU - Zhuge, Q.
AU - Su, D. M.
N1 - Funding Information:
Acknowledgements. We sincerely thank Dr. Dan Dimitrijevich (UNT-HSC at Ft. Worth) for carefully reading the manuscript, and Dr. Alea A Mills (Cold Spring Harbor Laboratory) for kindly providing the TAp63 cDNA. Flow cytometry was performed in the Flow Cytometry and Laser Capture Microdissection Core Facility at UNT-HSC, which was supported by NIH award ISIORR018999-01A1. This work was supported by NIAID/NIH grants (R01AI081995) to D-M S.
PY - 2013/11
Y1 - 2013/11
N2 - 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.
AB - 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.
KW - Conditional FoxN1 knockout
KW - Epithelial cell homeostasis
KW - Senescence
KW - Thymic aging
KW - p63/p53 expression
UR - http://www.scopus.com/inward/record.url?scp=84889604169&partnerID=8YFLogxK
U2 - 10.1038/cddis.2013.460
DO - 10.1038/cddis.2013.460
M3 - Article
C2 - 24263106
AN - SCOPUS:84889604169
SN - 2041-4889
VL - 4
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 11
M1 - e932
ER -