GENE TARGETING IN THE LG-KAPPA LOCUS - EFFICIENT GENERATION OF LAMBDA-CHAIN-EXPRESSING B-CELLS, INDEPENDENT OF GENE REARRANGEMENTS IN LG-KAPPA

The production of lambda chain-expressing B cells was studied in mice in which either the gene encoding the constant region of the chi chain (Cchi) or the intron enhancer in the Igchi locus was inactivated by insertion of a neomycin resistance gene. The two mutants have similar phenotypes: in heterozygous mutant mice the fraction of lambda chain-bearing B cells is twice that in the wildtype. Homozygous mutants produce approximately 7 times more lambda-expressing B cells (and about 2.3 times fewer total B cells) in the bone marrow than their normal counterparts, suggesting that B cell progenitors can differentiate into either chi- or lambda-producing cells and do the latter in the mutants. Whereas gene rearrangements in the Igchi locus are blocked in the case of enhancer inactivation, they still occur in that of the Cchi mutant, although in this mutant RS rearrangement is lower than in the wildtype. This indicates that gene rearrangements in the Iglambda locus can occur in the absence of a putative positive signal resulting from gene rearrangements in Igchi, including RS recombination. Complementing these results, we also present data indicating that in normal B cell development chi chain rearrangement can be preceded by lambda chain rearrangement and that the frequency of chi/lambda double producers is small and insufficient to explain the massive production of lambda chain-expressing B cells in the mutants.