Conversion of the Thymus into a Bipotent Lymphoid Organ by Replacement of Foxn1 with Its Paralog, Foxn4

• Vertebrate thymopoiesis requires expression of Foxn1/4 genes in thymic epithelium
• Phylogenic data suggest Foxn4 as the primordial regulator of vertebrate thymopoiesis
• Coexpression of Foxn4 and Foxn1 in mice generates a fish-like thymus
• Hypothetical primordial thymus exhibits spatially segregated T and B cell poiesis

SummaryThe thymus is a lymphoid organ unique to vertebrates, and it provides a unique microenvironment that facilitates the differentiation of immature hematopoietic precursors into mature T cells. We subjected the evolutionary trajectory of the thymic microenvironment to experimental analysis. A hypothetical primordial form of the thymus was established in mice by replacing FOXN1, the vertebrate-specific master regulator of thymic epithelial cell function, with its metazoan ancestor, FOXN4, thereby resetting the regulatory and coding changes that have occurred since the divergence of these two paralogs. FOXN4 exhibited substantial thymopoietic activity. Unexpectedly, histological changes and a functional imbalance between the lymphopoietic cytokine IL7 and the T cell specification factor DLL4 within the reconstructed thymus resulted in coincident but spatially segregated T and B cell development. Our results identify an evolutionary mechanism underlying the conversion of a general lymphopoietic organ to a site of exclusive T cell generation.

Graphical AbstractFigure optionsDownload as PowerPoint slide