FOXN1 in thymus organogenesis and development

Development of the primary T-cell repertoire takes place in the thymus. The linked processes of T-cell differentiation and T-cell repertoire selection each depend on interactions between thymocytes and thymic stromal cells; in particular, with the epithelial cells of the cortical and medullary thymic compartments (cortical and medullary thymic epithelial cells; cTECs and mTECs, respectively). The importance of the thymic epithelial cell lineage in these processes was revealed in part through analysis of nude (nu/nu) mice, which are congenitally hairless and athymic. The nude phenotype results from null mutation of the forkhead transcription factor FOXN1, which has emerged as a pivotal regulator both of thymus development and homeostasis. FOXN1 has been shown to play critical roles in thymus development, function, maintenance, and even regeneration, which positions it as a master regulator of thymic epithelial cell (TEC) differentiation. In this review, we discuss current understanding of the regulation and functions of FOXN1 throughout thymus ontogeny, from the earliest stages of organogenesis through homeostasis to age-related involution, contextualising its significance through reference to other members of the wider Forkhead family.