A NONIMMUNOGLOBULIN TRANSGENE AND THE ENDOGENOUS IMMUNOGLOBULIN-MU GENE ARE COORDINATELY REGULATED BY ALTERNATIVE RNA PROCESSING DURING B-CELL MATURATION

The immunoglobulin (Ig) genes have been extensively studied as model s ystems for developmentally regulated alternative RNA processing, Trans cripts from these genes are alternatively processed at their 3' ends t o yield a transcript that is either cleaved and polyadenylated at a si te within an intron or spliced to remove the poly(ii) site and subsequ ently cleaved and polyadenylated at a downstream site, Results obtaine d from expressing modified genes in established tissue culture cell li nes that represent different stages of B-lymphocyte maturation have su ggested that the only requirement for regulation is that a pre-mRNA co ntain competing cleavage-polyadenylation and splice reactions whose ef ficiencies are balanced. Since several non-Ig genes modified to have a n Ig gene-like structure are regulated in cell lines, Ig-specific sequ ences are not essential for this control, This strongly implies that c hanges in the amounts or activities of general RNA processing componen ts mediate the processing regulation, Despite numerous studies in cell lines, this model of Ig gene regulation has never been tested in vivo during normal lymphocyte maturation, We have now introduced a non-Ig gene with an Ig gene-like structure into the mouse germ line and demon strate that RNA from the transgene is alternatively processed and regu lated in murine splenic B cells. This establishes that the balance and arrangement of competing cleavage-polyadenylation reactions are suffi cient for RNA processing regulation during normal B-lymphocyte develop ment. These experiments also validate the use of tissue culture cell l ines for studies of Ig processing regulation, This is the first transg enic mouse produced to test a specific model for regulated mRNA proces sing.