TY - JOUR
T1 - Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice
AU - Ruan, L.
AU - Zhang, Z.
AU - Mu, L.
AU - Burnley, P.
AU - Wang, L.
AU - Coder, B.
AU - Zhuge, Q.
AU - Su, D. M.
N1 - Funding Information:
This work was partially supported by an NIAID/NIH grant (R01AI081995) to D-MS, and by the Foundation of Zhejiang Provincial Top Key Discipline of Surgery, National Natural Science Foundation of China (81371396) to QZ and National Natural Science Foundation of China (81400954) to LR.
Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - FoxN1 is cell-autonomously expressed in skin and thymic epithelial cells (TECs), essential for their development. Inborn mutation of FoxN1 results in hair follicle and TEC development failure, whereas insufficient postnatal FoxN1 expression induces thymic atrophy, resulting in declined T lymphopoiesis. Although upregulating FoxN1 expression in the aged FoxN1-declined thymus rejuvenates T lymphopoiesis, whether its over- and ectopic-expression in early life is beneficial for T lymphopoiesis is unknown. Using our newly generated Rosa26-STOPflox-FoxN1 mice, in which over- and ectopic-expression of FoxN1 can be induced by various promoter-driven Cre-mediated deletions of the roadblock STOPflox in early life, we found that K14Cre-mediated inborn FoxN1 overexpression induced neonatal lethality, exhibited abnormal permeability in the skin and abnormal nursing. Ubiquitous deletion of the STOPflox mediated by progressive uCreERT leakage in juvenile mice affected thymus and bone marrow normality, resulting in an increased ratio of medullary/cortical TECs, along with declined T and B lymphopoiesis. Although the K5CreERTmediated FoxN1 overexpression mice had a normal lifespan, induction of K5CreERT activation in juveniles adversely influenced= total thymoycte development and produced ichthyosis-like skin. Therefore, FoxN1 has temporal and tissue-specific activity. Overand ectopic-expression of FoxN1 in early life adversely influence immature TEC, T and B cell, and skin epithelial development.
AB - FoxN1 is cell-autonomously expressed in skin and thymic epithelial cells (TECs), essential for their development. Inborn mutation of FoxN1 results in hair follicle and TEC development failure, whereas insufficient postnatal FoxN1 expression induces thymic atrophy, resulting in declined T lymphopoiesis. Although upregulating FoxN1 expression in the aged FoxN1-declined thymus rejuvenates T lymphopoiesis, whether its over- and ectopic-expression in early life is beneficial for T lymphopoiesis is unknown. Using our newly generated Rosa26-STOPflox-FoxN1 mice, in which over- and ectopic-expression of FoxN1 can be induced by various promoter-driven Cre-mediated deletions of the roadblock STOPflox in early life, we found that K14Cre-mediated inborn FoxN1 overexpression induced neonatal lethality, exhibited abnormal permeability in the skin and abnormal nursing. Ubiquitous deletion of the STOPflox mediated by progressive uCreERT leakage in juvenile mice affected thymus and bone marrow normality, resulting in an increased ratio of medullary/cortical TECs, along with declined T and B lymphopoiesis. Although the K5CreERTmediated FoxN1 overexpression mice had a normal lifespan, induction of K5CreERT activation in juveniles adversely influenced= total thymoycte development and produced ichthyosis-like skin. Therefore, FoxN1 has temporal and tissue-specific activity. Overand ectopic-expression of FoxN1 in early life adversely influence immature TEC, T and B cell, and skin epithelial development.
UR - http://www.scopus.com/inward/record.url?scp=84928010278&partnerID=8YFLogxK
U2 - 10.1038/cddis.2014.432
DO - 10.1038/cddis.2014.432
M3 - Article
C2 - 25299782
AN - SCOPUS:84928010278
SN - 2041-4889
VL - 5
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 10
M1 - e1457
ER -