Role of the forkhead transcription family member, FKHR, in thymocyte differentiation

While performing a large-scale analysis of mRNA transcripts in the murine t hymus, our attention was drawn to the forkhead family transcription factor FKHR. Here we demonstrate that FKHR is expressed in thymocytes, most promin ently in those that are undergoing positive selection. Interestingly, FKHR transcripts show a highly regionalized pattern of expression, concentrated in the innermost areas of the medulla. We define the FKHR binding site as ( G/C)(A/C)N(G/a)T(A/c)AA(T/c)A(T/g)(T/g)(G/c), a sequence found in the regul atory elements of many genes, including certain that encode molecules cruci al for thymocyte differentiation. To study the function of FKHR, we enginee red mice expressing a dominant-negative mutant specifically in T cells in a tetracycline-regulatable fashion. In these animals, T cell differentiation appeared quite normal; however, total thymocyte numbers were decreased, ow ing to reductions in all four of the CD4/CD8 subsets, and incorporation of the thymidine analogue bromo-deoxyuridine was increased, again in all four subsets. These data suggest that, in thymocytes, FKHR may be involved in ce ll survival and/or cycling.