Control of Lineage Commitment in Developing Thymocytes

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DESCRIPTION (provided by applicant): The overall aim of this project is to understand the mechanisms that control alternative commitment of alpha/beta thymocytes to the CD4 or CD8 lineages and that ensure the precise correlation between coreceptor expression and TCR restriction to class I or II MHC. Although it is now widely accepted that alternate TCR signaling in response to engagement by class I or II ligands is responsible for initiating alternate lineage commitment, the intracellular pathways through which this is accomplished remain unknown. We have previously described a unique spontaneous mutant mouse, termed "helper deficient" or HD, in which the correlation between coreceptor expression and MHC specificity breaks down, such that all thymocytes, in particular class II-restricted ones, adopt the CD8 lineage. We have now tentatively identified the defective gene as cKrox, a largely uncharacterized member of the POK subfamily of proteins, which are defined as containing both a Kr
ppel-like zinc finger and a BTB/POZ domain, the latter implicated in transcriptional repression. Based on this very recent finding, the current proposal focuses on defining the functional characteristics, regulation and cellular distribution of cKrox in developing thymocytes. We propose the following specific aims: 1) To definitively demonstrate that cKrox corresponds to the HD locus. 2) To determine how cKrox activity is differentially regulated in class I- versus class II-specific thymocytes. 3) To functionally dissect the roles of the zinc finger and BTB/POZ domains of cKrox in lineage commitment.