Effect of upstream RNA processing on selection of μS versus μM poly(A) sites

All of the regulatory factors responsible for augmenting mu S mRNA levels preceding the dramatic increase in secretory IgM production upon B cell activation has not been totally elucidated. Whereas previous experiments have centered on the region of the gene specifying the choice between splicing to mu M exons versus selection of the mu S poly(A) site, we have found that upstream sequences within the C mu gene, specifically the C mu 4 acceptor splice site together with intronic sequences between the C mu 3 and C mu 4 exons, play an important role in dictating the precision or the extent of splicing to the mu M exons even under conditions in which functional polyadenylation factors should be in excess. Therefore, splicing of upstream exons can affect remotely located downstream exons. These findings suggest that regulation of differential mu S/mu M mRNA expression may involve general processing enzymes that recognize specific cis-regulatory sequences residing within the body of the mu gene and account for the unique ability of activated B cells to secrete copious amounts of IgM.