Foxn1 overexpression promotes thymic epithelial progenitor cell proliferation and mTEC maintenance, but does not prevent thymic involution
The transcription factor FOXN1 is essential for fetal thymic epithelial cell (TEC) differentiation and proliferation. In the postnatal thymus, Foxn1 levels vary widely between different TEC subsets, from low or undetectable in putative TEC progenitors to highest in the most differentiated TEC subsets. Correct Foxn1 expression is also required to maintain the postnatal microenvironment, as premature down-regulation of Foxn1 causes a rapid involution-like phenotype, while transgenic over-expression can cause thymic hyperplasia and/or delayed involution. In the current study, we investigated a K5.Foxn1 transgene that drives Foxn1 over-expression in TECs, but does not cause hyperplasia, nor does it delay or prevent aging-related involution. Similarly, this transgene cannot rescue thymus size in Foxn1lacZ/lacZ mice that undergo premature involution due to reduced Foxn1 levels. However, K5.Foxn1 transgenics do maintain TEC differentiation and cortico-medullary organization with aging both alone and in hypomorphic Foxn1lacZ/lacZ mice. Analysis of candidate TEC markers showed co-expression of progenitor and differentiation markers as well as increased proliferation in Plet-1+ TECs associated with Foxn1 expression. These results demonstrate that the functions of FOXN1 in promoting TEC proliferation and differentiation are separable and context-dependent, and suggest that modulating Foxn1 levels can regulate the balance of proliferation and differentiation in TEC progenitors.