The proposed studies are aimed at the elucidation of mechanisms that control precursor lymphocyte differentiation with a particular focus on factors that regulate antigen receptor variable region gene assembly (VDJ recombination). Cloned VDJ recombination substrates will be introduced into transgenic or chimeric animals to elucidate elements that control stage and lineage-specificity of VDJ recombinase activity within the lymphoid lineages. Other types of VDJ recombination substrates will be transfected into VDJ recombinase-positive cell lines to study molecular details of how particular elements defined in transgenic assays influence accessibility of substrate gene segments to VDJ recombinase. A particular focus of the latter studies will be to generate novel pre-B lines that provide a more physiologically representative system for these assays. Novel cellular and animals models will be generated to study factors involved with the progression of cells through the precursor stages of the B cell differentiation pathway. Animal models will include mice unable to assemble endogenous immunoglobulin heavy chain genes and mice that constitutively express VDJ recombination enzymes throughout B cell differentiation; these systems will permit elucidation of the function and control of ordered assembly of immunoglobulin heavy and light chain genes and help elucidate the function and regulation of allelic exclusion.
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