Abstract
BackgroundThe Nonsense-Mediated mRNA Decay (NMD) pathway detects and degrades mRNAs containing premature termination codons, thereby preventing the accumulation of potentially detrimental truncated proteins. Intertissue variation in the efficiency of this mechanism has been suggested, which could have important implications for the understanding of genotype-phenotype correlations in various genetic disorders. However, compelling evidence in favour of this hypothesis is lacking. Here, we have explored this question by measuring the ratio of mutant versus wild-type Men1 transcripts in thirteen tissues from mice carrying a heterozygous truncating mutation in the ubiquitously expressed Men1 gene.ResultsSignificant differences were found between two groups of tissues. The first group, which includes testis, ovary, brain and heart, displays a strong decrease of the nonsense transcript (average ratio of 18% of mutant versus wild-type Men1 transcripts, identical to the value measured in murine embryonic fibroblasts). The second group, comprising lung, intestine and thymus, shows much less pronounced NMD (average ratio of 35%). Importantly, the extent of degradation by NMD does not correlate with the expression level of eleven genes encoding proteins involved in NMD or with the expression level of the Men1 gene.ConclusionMouse models are an attractive option to evaluate the efficiency of NMD in multiple mammalian tissues and organs, given that it is much easier to obtain these from a mouse than from a single individual carrying a germline truncating mutation. In this study, we have uncovered in the thirteen different murine tissues that we examined up to a two-fold difference in NMD efficiency.
Highlights
The Nonsense-Mediated Messenger RNA (mRNA) Decay (NMD) pathway detects and degrades mRNAs containing premature termination codons, thereby preventing the accumulation of potentially detrimental truncated proteins
Men1+/Δ mouse embryonic fibroblasts (MEF) were used to verify that premature termination codons (PTCs)-containing Men1 transcripts were subjected to Nonsense-Mediated mRNA Decay (NMD) as expected, given the presence of six exon-exon junctions downstream of the PTC
We found by real time quantitative RT-PCR that mutant transcripts were present at levels of 18% and 60% of their wild-type counterpart without and with the NMD inhibitor puromycin, respectively (Figure 1b)
Summary
The Nonsense-Mediated mRNA Decay (NMD) pathway detects and degrades mRNAs containing premature termination codons, thereby preventing the accumulation of potentially detrimental truncated proteins. Messenger RNA (mRNA) quality control is essential to assure the fidelity of gene expression. It is achieved through several mechanisms among which NonsenseMediated mRNA Decay (NMD) plays a major role. The NMD pathway detects and degrades mRNAs containing (page number not for citation purposes). BMC Genetics 2008, 9:83 http://www.biomedcentral.com/1471-2156/9/83 premature termination codons (PTCs), thereby preventing the accumulation of potentially harmful truncated proteins [1]. PTC recognition depends upon the position of the stop codon within the transcript. Recognition is thought to occur during a pioneering round of translation, and exon-exon boundaries are delimited on the transcript by exon-exon junction complexes (EJCs) deposited during splicing [3]
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