Over-, ectopic-expression of FoxN1 at early life adversely influences lymphopoiesis (HEM3P.280)

Abstract

Abstract FoxN1 expresses in thymic epithelial cell (TEC) and skin epithelium to regulate their development. Prenatal mutation in FoxN1 results in thymic development failure and nude phenotype, while postnatal insufficient FoxN1 expression induces thymic atrophy, resulting in declined T-lymphopoiesis. Although enhancing FoxN1 expression in aged thymus promotes functional rejuvenation, whether FoxN1 over-expression at early age or ectopic expression in the bone marrow is beneficial for lymphopoiesis is unknown. Using our newly generated R26-STOPflox-FoxN1 (gain-of-function) mutant mice, which have an over-expressed FoxN1 after various promoter-driven Cre-mediated deletion of the roadblock STOPflox, we found that K14Cre-mediated prenatal FoxN1 over-expression resulted in a newborn lethal phenotype, displaying abnormal permeability in the skin. Ubiquitous deletion of the STOPflox mediated by uCreERT progressive leak in infant mice influenced TEC development, and T- and B-lymphopoiesis. Although the K5CreERT mediated FoxN1 over-expression in adult mice may be beneficial for postponing thymic aging, early induction of K5CreERT activation in infants induced adverse influences to thymoycte and hair follicle development. Therefore, FoxN1 has a stage and tissue sensitivity. Over- and ectopic-expression of FoxN1 at early life adversely influences immature thymic, T-, and B-cell, and skin epithelial development.