Regulation of eukaryotic gene expression through functional coupling between alternative splicing and nonsense-mediated decay

Alternative pre-mRNA splicing (AS) and nonsense-mediated decay (NMD) are key RNA-based regulatory mechanisms in eukaryotic cells. Although NMD was initially identified as a quality-control pathway targeting aberrant transcripts, increasing evidence indicates that it frequently operates in concert with genetically programmed AS to regulate the expression output of protein-coding genes. Here, we describe AS-NMD mechanisms, highlighting their diverse functions across biological contexts. These include roles in maintaining cellular homeostasis, preventing premature expression of differentiation-specific genes, sharpening gene expression dynamics during development, and fine-tuning responses to physiological cues. We additionally summarize experimental approaches used to study AS-NMD and discuss possible evolutionary mechanisms underlying the acquisition of new regulatory AS-NMD events and their integration into gene regulatory networks. Overall, this review provides a unified perspective on AS-NMD as a widespread, multifaceted, and evolutionarily dynamic regulator of gene expression at the post-transcriptional level.