Regulation of nuclear poly(A) addition controls the expression of immunoglobulin M secretory mRNA

B-cell differentiation is accompanied by a dramatic increase in cytoplasmic accumulation and stability of the IgM heavy chain (mu) secretory mRNA. Despite considerable effort, the mechanism is unknown. We have identified three short motifs upstream of the secretory poly(A) site, which, when mutated in the mu heavy chain gene, significantly increase the accumulation of the secretory form of poly(A)(+) mRNA relative to the membrane form and regulate the expression of the secretory poly(A) site in a developmental manner. We show that these motifs bind U1A and inhibit polyadenylation in vitro and in vivo. Overexpression of U1A in vivo results in the selective inhibition of the secretory form. Thus, this novel mechanism selectively controls post-cleavage expression of the mu secretory mRNA. We present evidence that this mechanism is used to regulate alternative expression of other genes.