We have used a genetic approach to study the differentiation of B lymphocytes. Our model system is the induction of membrane immunoglobulin M-positive (mIgM+) cells in the murine B cell tumor, 70Z/3 by three extracellular mediators: lipopolysaccharide (LPS), supernatants from concanavalin A-stimulated rat spleen cells (CAS) and gamma interferon (IFN). The wild-type 70Z/3 cells synthesize constitutively the mu immunoglobulin heavy chain, but the kappa (kappa) light chain is expressed at extremely low levels. Treatment with these three inducers markedly increases kappa synthesis and allows the expression of IgM on the cell surface. We have selected variants which respond aberrantly to LPS and have analyzed their responses to the other inducers. We have analyzed mIgM expression, mu and kappa mRNA and protein levels. Our results show that the level of kappa mRNA is the most sensitive indicator of cellular response to an inducer. The independence of the variant phenotypes demonstrates that the pathways are not identical.