Abstract
BackgroundNonsense-mediated mRNA decay (NMD) is a post-transcriptional RNA surveillance process that facilitates the recognition and destruction of mRNAs bearing premature terminations codons (PTCs). Such PTC-containing (PTC+) mRNAs may arise from different processes, including erroneous processing and expression of pseudogenes, but also from more regulated events such as alternative splicing coupled NMD (AS-NMD). Thus, the NMD pathway serves both as a silencer of genomic noise and a regulator of gene expression. Given the early embryonic lethality in NMD deficient mice, uncovering the full regulatory potential of the NMD pathway in mammals will require the functional assessment of NMD in different tissues.Methodology/Principal FindingsHere we use mouse genetics to address the role of UPF2, a core NMD component, in the development, function and regeneration of the liver. We find that loss of NMD during fetal liver development is incompatible with postnatal life due to failure of terminal differentiation. Moreover, deletion of Upf2 in the adult liver results in hepatosteatosis and disruption of liver homeostasis. Finally, NMD was found to be absolutely required for liver regeneration.Conclusion/SignificanceCollectively, our data demonstrate the critical role of the NMD pathway in liver development, function and regeneration and highlights the importance of NMD for mammalian biology.
Highlights
The Nonsense-mediated mRNA decay (NMD) machinery is part of a larger set of RNA surveillance pathways that check the integrity of mRNAs before rendering them available for translation in the cytoplasm
Ablation of NMD in the developing liver leads to perinatal lethality Mice deficient of the core NMD component UPF2 die in utero around E3.5-E7.5 [13]
Similar to what we found in the fetal liver, Gene Set Enrichment Analysis (GSEA) (See Table S6 for the full analysis) revealed that loss of UPF2 in the adult setting led to down-regulation of genes involved in ‘‘HSA04610 Complement and Coagulation cascades’’ and metabolic pathways as exemplified by ‘‘Biosynthesis of Steroids’’ albeit at less significance as what resulted from embryonic loss of UPF2 (Figure 5G)
Summary
The NMD machinery is part of a larger set of RNA surveillance pathways that check the integrity of mRNAs before rendering them available for translation in the cytoplasm. As most mammalian genes carry their termination codon in the last exon, a stop codon located upstream of an EJC marks it as premature. Nonsense-mediated mRNA decay (NMD) is a post-transcriptional RNA surveillance process that facilitates the recognition and destruction of mRNAs bearing premature terminations codons (PTCs). Such PTC-containing (PTC+) mRNAs may arise from different processes, including erroneous processing and expression of pseudogenes, and from more regulated events such as alternative splicing coupled NMD (AS-NMD). Given the early embryonic lethality in NMD deficient mice, uncovering the full regulatory potential of the NMD pathway in mammals will require the functional assessment of NMD in different tissues
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