An illustrative example with important ramifications is AUF1, which targets mRNAs containing AU-rich elements (AREs) for rapid cytoplasmic turnover. Alternative splicing generates five variants of AUF1 mRNA, which have different 3′UTRs. The generation of alternative 3′UTR can affect AUF1 expression by two mechanisms: AUF1 protein directly binding AUF1 3′UTR splice variants that retain intron 9 (affected by the alternative splicing), and activation of the mRNA NMD pathway. Two of the AUF1 3′UTR variants position the translational termination codon more than 50 nucleotides upstream of an exon-exon junction, creating a potential triggering signal for NMD. Disruption of cellular NMD pathways by gene specific knockdown enhanced the mRNA expression of these two AUF1 isoforms, with stabilization of each transcript. Additionally, quantification of AUF1 mRNA 3′UTR splice variants during murine embryonic development showed that the expression of NMD-sensitive AUF1 mRNAs is specifically enhanced as development proceeds, contributing to dynamic changes in AUF1 3′UTR structures during embryogenesis.93
