One of the earliest events in thymocyte differentiation is expression of the CD3 genes of the TCR/CD3 complex mediated by transcription factors that become activated as part of the T cell developmental program. Expression of one or more of these T cell restricted nuclear factors may dictate commitment and differentiation of a hemopoietic progenitor into the T cell lineage. In search of the tissue specific mediators of transcription for the CD3delta gene we have identified a unique T cell restricted zinc finger DNA binding protein with sequence similarities and zinc finger organization to the Drosophila Gap gene Hunchback. The Ikaros protein bind and activates the CD3delta enhancer confirming our hypothesis that it can regulate expression of this early but definitive T cell differentiation antigen. The expression pattern of the Ikaros gene suggests a fundamental role in T cell development. In the adult mouse Ikaros expression is restricted in cells of the T lineage. During mouse embryogenesis, Ikaros is first detected in the fetal liver at a time when hemopoietic progenitors are proliferating in this tissue and prior to development of the thymus. Strong expression is observed in the thymus from the time that T cell progenitors first populate this tissue and continues throughout development. The profile of expression and ability of Ikaros to stimulate transcription of T cell markers suggest that Ikaros could mediate commitment of a hemopoietic progenitor to the lymphoid/T cell lineage. A number of Ikaros splicing variants were isolated encoding for proteins with distinct DNA binding domains. In the following studies the expression of the Ikaros isoforms will be addressed in purified hemopoietic populations and during embryogenesis to determine when and where they become expressed and whether they are responsible for regulating distinct developmental programs in the hemopoietic lineage. Their binding and transcription properties will be studied to identify putative target sites in T cell restricted genes and to delineate the molecular mechanism by which they exert their function. The possible involvement of the Ikaros gene in causing leukemias will be investigated by cloning and genome mapping the human homologue Finally the role of the Ikaros gene in the development of hemopoietic lineages will be studied by expression studies in embryonic stem cells in vitro and by gene ablation studies in intact animal models.
NIH ExPorter
NIH ExPorter