ALTERNATIVE PROCESSING OF IGA PRE-MESSENGER-RNA RESPONDS LIKE IGM TO ALTERATIONS IN THE EFFICIENCY OF THE COMPETING SPLICE AND CLEAVAGE POLYADENYLATION REACTIONS

Both the membrane-associated and -secreted Ig proteins are encoded by a single gene whose primary transcript is alternatively processed at i ts 3' end. The relative use of the alternative processing pathways is regulated during B cell maturation. This alternative RNA processing in volves two competing reactions, splicing from the last constant region exon to the membrane exon(s) and cleavage-polyadenylation at the secr etory-specific poly(A) site. Studies with the IgM-encoding mu gene hav e shown that cell-specific regulation requires that the efficiencies o f these two reactions be balanced; any gene modifications that substan tially improve or reduce the efficiency of either reaction also abroga te the regulatory shift in alternative processing pathways. All of the Ig isotypes that undergo a membrane-to-secreted switch during B cell maturation have a similar gene structure, thus suggesting that they mi ght all be regulated by the same mechanism. We show that RNA processin g of chimeric mu alpha genes containing modifications in the C alpha 3 exon size and the C alpha 3-alpha m intron size respond to these modi fications as predicted by previous mu gene studies. In addition, RNA e xpression ratios from the chimeric per genes are regulated in B cells and plasma cells. This provides good evidence that splicing and cleava ge-polyadenylation in the a gene are balanced reactions that are regul ated in the same way as in the mu gene.