Embryogenesis is orchestrated by temporal and cell type-specific changes in gene expression that are typically thought to be regulated by shifts in transcription rate. However, mRNA levels are additionally shaped by RNA decay rate, which may also play a role in embryogenesis. Now, Heidi Cook-Andersen, Miles Wilkinson and colleagues dissect the role of the RNA turnover pathway, nonsense-mediated RNA decay (NMD), the loss of which has previously been shown to cause early embryonic lethality in diverse species. They mutate the gene encoding the NMD factor regulator of nonsense transcripts 2 (UPF2) in mice and pinpoint the lethality to the peri-implantation stage. They identify a large cohort of NMD target mRNAs that encode proteins functioning in cell survival and proliferation, and uncover a selective defect in epiblast cells in the inner cell mass (ICM) in Upf2-null blastocysts, which exhibit rapid ICM regression and an inability to derive embryonic stem cells. They also discover that the magnitude of NMD pathway activity is increased during peri-implantation development, suggesting that transient degradation of target mRNAs is critical at this time. Together, these data demonstrate that UPF2 is crucial for early embryo development, with a stage-specific and lineage-specific role in promoting the progression of cells of the pluripotent epiblast.
