Mammalian Gene PEG10 Expresses Two Reading Frames

Paternally expressed gene 10 (PEG10) is a mammalian gene that is essential for embryonic development in mice. The gene contains two overlapping open reading frames (ORF1 and ORF2) and is derived from a retroelement that acquired a cellular function. It is not known if both reading frames are required for PEG10 function. Synthesis of ORF2 would be possible only if programmed 1 frameshifting occurredduringORF1 translation. In this study the frameshifting activity of PEG10 was analyzed in vivo, and a potential role for ORF2 was investigated. Phylogenetic analysis demonstrated that PEG10 is highly conserved in therian mammals, with all species retaining the elements necessary for frameshifting aswell as functionalmotifs in eachORF. The frameshift site ofPEG10washighly active in cultured cells andproduced the ORF1-2 protein. In mice, endogenous ORF1 and an ORF1-2 frameshift protein were detected in the developing placenta and amniotic membrane from 9.5 days post-coitus through to term with a very high frameshift efficiency (>60%). Mutagenesis of the active site motif of a putative protease within ORF2 showed that this enzyme is activeandparticipates inpost-translationalprocessing of PEG10ORF1-2. Both PEG10 proteins were also detected in first trimesterhumanplacenta.Bycontrast,neitherproteinexpression nor frameshifting was detected in adult mouse tissues. These studies imply that the ORF1-2 protein, synthesized utilizing the most efficient 1 frameshift mechanism yet documented in vivo, will have an essential function that is intrinsic to the importance of PEG10 inmammals.