Balanced efficiencies of splicing and cleavage-polyadenylation are required for mu-s and mu-m mRNA regulation.

The relative abundance of the RNAs encoding the membrane (mu-m) and secreted (mu-s) forms of immunoglobulin mu heavy chain is regulated during B cell maturation by a change in the mode of RNA processing. This regulation depends on a competition between two mutually exclusive RNA processing reactions, cleavage-polyadenylation at the microseconds poly(A) site and splicing of the Cmu4 and M1 exons. Previously, the efficiencies of these two reactions were altered independently. When an efficient processing signal replaced the normal suboptimal signals of the mu gene, a single RNA product was produced exclusively. In this report, two efficient signals are combined in a single mu transcript and shown to restore a processing balance such that two mRNAs can once again be alternatively processed from a single RNA precursor. The ratio of the two RNAs generated from these mu genes containing balanced competing strong splice and cleavage-polyadenylation reactions display the expected developmental shift when expressed in B cells and plasma cells. Therefore, the balance between cleavage-polyadenylation and splicing efficiencies is critical to the developmentally regulated expression of mu-s and mu-m mRNA. Also shown here is that the entire mu-m region, including the M1 and M2 exons and the mu-m poly(A) site, can be replaced with SV40 splice and poly(A) sequences. Regulation is maintained in these mu genes, indicating that no specific sequences within the mu-m region are required.