PEG10-ORF1 programs trophoblast progenitor development for placental labyrinth formation

The emergence of the placenta was a significant event in mammalian evolution, enabling therian mammals to give birth to live young through viviparity. A key genomic change associated with this process was likely the acquisition of the therian-specific paternally expressed 10 (PEG10) from a metavirus, as Peg10-null mutant mice exhibit early embryonic lethality due to the absence of both the spongiotrophoblast and labyrinth layers in the placenta. PEG10 encodes a GAG-like open reading frame 1 (ORF1) and a POL-like ORF2, and produces two proteins, PEG10-ORF1 and PEG10-ORF1/2 fusion proteins, via the -1 frameshift mechanism conserved in retroviruses and metaviruses. Here, we demonstrate PEG10-ORF1 plays an essential and distinct role in labyrinth development. Mice lacking ORF1 but retaining the ORF1/2 protein initially developed normally in both embryos and placentas; however, later exhibited underdevelopment of the placental labyrinths complex microarchitecture, accompanied by mid-to late gestational growth retardation and lethality. These severe defects are most likely attributable to dysregulated development of labyrinth trophoblast precursor (LaTP) cells. Beyond its essential role in early placental formation, we previously demonstrated that the DSG protease domain within PEG10-ORF1/2--a metaviruse-derived feature--is critical for maintaining fetal capillaries during late gestation. Thus, PEG10 fulfills multiple indispensable functions in placental formation and maintenance by exploiting a metavirus-derived multi-protein and -peptide production system, despite being a single gene. This study provides additional evidence underscoring the profound role of PEG10 acquisition in therian placental evolution. Significance StatementThe placenta is an essential organ for viviparous reproduction in therian mammals; therefore, its evolutionary emergence is of significant interest. One key event may have been the acquisition of PEG10, a metavirus (retrovirus-like LTR retrotransposon)- derived gene, by the common therian ancestor. We previously showed that Peg10 is required for early placental development and that its protease domain is essential for late-gestational maintenance of fetal capillaries within the placental labyrinth. Here, we provide additional genetic evidence that Peg10 is also indispensable for mid-gestational development of the placental labyrinthine microvasculature. Together, these findings illustrate how multiple, stage-specific functions of a single metavirus-derived gene, PEG10, coordinate placental formation and maintenance, highlighting the evolutionary importance of PEG10 acquisition in therian placentation.