ROLE OF MU-HEAVY-CHAIN IN B-CELL DEVELOPMENT - I - BLOCKED B-CELL MATURATION BUT COMPLETE ALLELIC EXCLUSION IN THE ABSENCE OF IG-ALPHA BETA/

There is good evidence for a signaling role played by Ig heavy chain i n the developmental transition through the pre-B cell stage. We have p reviously described signal-capable or signal-incapable mutants of mu h eavy chairs in which a signaling defect is caused by failure to associ ate with the Ig alpha/beta heterodimer. To further characterize the ro le of Ig heavy chain-mediated signaling in vivo, as well as in B cell development and allelic exclusion, we have created transgenic mice in which the B cells express these signal-capable and signal-incapable mu tant mu chains. Failure of la to signal via Ig alpha/beta results in a block in B cell development in mice expressing the signal-incapable m u. A small number of B tells in these animals do escape the developmen tal block and are expressed in the spleen and the periphery as B220(+) transgenic IgM(+) cells, These cells respond to LPS by proliferating but show no response to T-independent-specific Ag, In contrast, B cell s expressing the signal-capable B cell receptor show a strong signalin g response to Ag-specific stimulus. These is no Ig alpha seen in assoc iation with signal-deficient IgM, Thus, the B cell receptor complex is not assembled, and no signal cain be delivered. Despite the block in developmental signaling, allelic exclusion is complete. There is no de tectable coexpression of transgenic IgM and endogenous murine IgM, nor is there rearrangement of the endogenous heavy chain genes, This sugg ests that differing signaling mechanisms are responsible for the devel opmental transition and allelic exclusion and thus allows for separate examination of these signaling mechanisms.