FUNCTIONAL STUDIES OF IMMUNOGLOBULIN KAPPA ENHANCERS

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Immunoglobulin heavy (IgH) and light chain (IgL) genes are assembled through the somatic assembly of the variable (V), diversity (D) and joining (J) gene segments during the early stage of B cell differentiation. Two IgL chains, kappa and lambda, are present in mice. It appears that IgH and IgL chain genes are rearranged in a sequential manner such that IgH rearranges earlier than Igkappa while Igkappa rearranges earlier than Iglambda. Two enhancers, originally characterized by their ability to activate B-cell specific transcription, have been identified in the Igkappa locus. One of the enhancer is located in the intronal region between Jkappa and Ckappa (iEkappa) and the other located 3' of Ckappa (3'Ekappa). Employing homologous recombination and LoxP-Cre-mediated deletion, we and others have shown that both enhancers are quantitatively important but not essential for the Igkappa rearrangement. More importantly, both enhancers appear to be involved in the determination of the earlier rearrangement of Igkappa versus Iglambda. Based on these initial findings and employing the same methodology, we propose to dissect the functional motifs within iEkappa in the Igkappa rearrangement and to test the potential redundant functions of iEkappa and 3'Ekappa in the Igkappa rearrangement and expression. In addition, transgenic studies have suggested that both K enhancers are critical for somatic hypermutation of Igkappa. We will again employ genetic approaches to further explore the functions of MiEkappa in somatic hypermutations of Igkappa in a physiological context.