Rent1, a trans-effector of nonsense-mediated mRNA decay, is essential for mammalian embryonic viability

The ability to detect and degrade transcripts that lack full coding potenti al is ubiquitous but non-essential in lower eukaryotes, leaving in question the evolutionary basis for complete maintenance of this function, One hypo thesis holds that nonsense-mediated RNA decay (NMD) protects the organism b y preventing the translation of truncated peptides with dominant negative o r deleterious gain-of-function potential. All organisms studied to date tha t are competent for NMD express a structural homolog of Saccharomyces cerev isiae Upf1p, We have now explored the consequences of loss of NMD function in vertebrates through targeted disruption of the Rent1 gene in murine embr yonic stem cells which encodes a mammalian ortholog of Upf1p. Mice heterozy gous for the targeted allele showed no apparent phenotypic abnormalities bu t homozygosity was never observed, demonstrating that Rent1 is essential fo r embryonic viability, Homozygous targeted embryos show complete loss of NM D and are viable in the pre-implantation period, but resorb shortly after i mplantation, Furthermore, Rent1(-/-) blastocysts isolated at 3.5 days post- coitum undergo apoptosis in culture following a brief phase of cellular exp ansion. These data suggest that NMD is essential for mammalian cellular via bility and support a critical role for the pathway in the regulated express ion of selected physiologic transcripts.