Placentas are most diverse organs across mammalian species. Although the mammals obtained several new genes specific to pregnancy recognition and/or maintenance, which are often species’ specific, gene expressions for placental development and/or their structural diversity have not been well characterized. It has long been thought that viraluses/transposons components exist in organism’ genomes. In 2000, Mi et al., found that endogenous retrovirus (ERV, Syncytin-1) exists in the human placenta ^[1]. Since then, syncytin-typlike ERV structures and their functions have been reported in many animal species ^[2][3][4], but none of them contain the same nucleotide structures, strongly suggesting that these ERVs are independently captured and integrated into mammalian genomes. ^[5].

MThese observammaltian placentas are extraordinarilyons revealed that structural diverse in terms of cell types, structure aity could be explained by these syncytin-like ERVs.

Ind their association with maternal blood, althoughis review, we presented sufficient evidence that the evolution of placentas play the same roles such as physical and immunological protection against the m or placental structures requires PEG10 and PRG11/RTL1, paternal immune system, nutrient and gas exchangly expressed imprinted genes, and endocrinological regulation ^[6]. Dstructuring the alast several decades, scientists in developmental biology and/or virologists have occasionally proposed retrovirus’s role in placental evolution. For example, Haig (2012) proposed that the placenta became a mammalian tissue in which retrovira diversity comes from the syncytin-like ERVs. We also presented recent observations on ERVs and how these ERVs control genes were domesticated to serve an adaptive expression of both function in the host ^[7]. Suchal genes ans interplay may have contributed to evolutionally mechanisms associated with genomic imprinting of numerous genes.

Figure legend: Mawell as ERV themselves. Based on the recent informmalian placentas as classified by the distribution of chorionic villi. A: Difftion, we presented the baton-pass hypothesis, successe placentas to which pigive integration of ERVs and horses belong.new models explaining B: Cotyledonary placentas, commonly found in rumin diversity.

Babant, ungulates.K.; C: ZonNakary placentas to which dogs and cats belong.a, Y.; Shojima, T.; Muroi, Y.; D: DKiscozakid placentas, seen in murine and primate species including humans, K.; Hashizume, K.; Imakawa, K.; Miyazawa, T.

Impridenting genes such as those of paternaification of novelly

expressend genes, PEG10 ^[8] and PEG11/RTL1ogenous ^[9], have betaren extensively studied for their contribution to the evolutional development of mammalian species. Through gene troviruses which are transcribed in the bovine placenta. J. Virol. 2011, 85, 1237–1245.

Chabrlation studies, these genes are found necessary for the formation of placental structures ^[10][11]ier, C.; Segers, K.; Wagenaar, D.; Karim, L.; Berghmans, S.; Jaillon, O.; Because PEG10 is acquired more than 146 million years agoShay, T.; Weissenbach, J.; Cockett, N.; Gyapay, PEG10 geneG.; could explain the initial fort al.

Humatn-ovion of placentas in mammals. However, structural diversity of placentas cannot be explained through the integration and function of PEG10 ne comparative sequencing of a 250-kb imprinted domain encompassind PEG11/RTL1 genes. The phylogenetic record shows multiple independent instathe callipyge (clpg) locus and identificationces

of syncytin-type ERV genes’ entry into disparate clades over the last 50 million yearsx imprinted transcripts: DLK1, DAT, GTL2, ^[5]PEG11, stroangly suggesting thattiPEG11, and syncytin-typeMEG8. gGenes as prime candidates for tome. Res. 2001, 11, 850–862.

Che emergence of structural diversification of mammalianong, E.B. The placentas. Recently, more and more data have been accumulated, demonstrating that syncytin-typ goes viral: Retroviruse ERVs control gene expression of both functional gein pregnancy. PLoS Biol. 2018, 16, e3000028.

Cornelis as well as, G.; Heidmann, ERVO.; thDemselvesgrelle, ^[12][13]S.A.; It is often observed thatVernochet, C.; Lavialle, C.; Letzelter, ERVC.; intBegrations into mammalian genomes proceed successively: one ERV exaprnard-Stoecklin, S.; Hassanin, A.; Mulotation, B.;

Guis followed by successive invasions of new ERVsomot, M.; et al. The new inCapterloperured retroviral genes may subsume the role previousenvelope ERVs played. These ongoing and successive ERVncytin gene acquisitions for the establishment of more advantageous systems are explained by “a baton pass hypothesis”sociated with the ^[14].

Iun giqueneral, the placentas have lower DNA methylation levels than embryos, allowing freel structure of higher exp

ressumion of ERVs nand transposons during gestation, thereby facilitating selection of s. Proc. Natl. Acad. Sci. USA 2013, 110, E828–E837.

Dewadvantageous genes from a wider market. Such extraembryonic circumstances might have allowed for not only domestication of ERVnieux, M.; Heidmann, T. Endogenous to restablish novel endogenous genes via multiple of selections but also the dissemination oftroviruses: Acquisition, amplification ERVs and transposons throughoutming of genomes as transcript invaders. Curr Opin

Vironal regulatorsl 2013, 3, 646–656. Si

Imilakawarly, various degrees of maternal-fetal cell interactions in the uterine compartment may have led to change in kinds and degree of gene usage, K.; Nakagawa, S.; Miyazawa, T. Baton pass hypothesis: Successive incorporation of unconserved endogenous ^[7], possibly resulting in cellular and morphologicroviral chan

ges in placentas. It is interesting to speculate that the placentas themselves might have served as an evolutionary laboratory to promote es for placentation during mammalian evolution. ^[15].

ThGe outner most cell layer at the fetal side of placentas is called “trophectoderm”s Cells 2015, 20, 771–788. Across

Imammkalian species, the trophectodermal cells exhibit a great deal of fusogenic activity, notwithstanding the huge diversity in placental structures and type of placentation such as invasive (humans and murine) or non-invasive (pigs and ruminants) wa, K.; Bai, R.; Fujiwara, H.; Ideta, A.; Aoyagi, Y.; Kusama, K. Continuous model of conceptus implantation to the maternal

endometrium. BaseJ. End on actual experocrinol. 2017, 233, R53–R65

Kimentation and typical amino acid sequences, ERVs’ funco, K.; Nakagawa, S.; Miyazawa, T. An ancientions are generally limited to fusogenic activity and immunotolerance, which on their own are not sufficient to fully explain the structural diversity of placentas.

Dunn-Fletcherretroviral RNA element hidden in mammalian genomes and its involvement aind

colleagues (2018) have dem-onstrated that pted retroviral THE1B sgequence serves as a cis-element for the ree regulation of corticotropin-releasing hormone (CRH). Retrovirology 2021, 18, gene express36.

Mion, ^[16]S.; Recently, progress has been made on research into ERV sequeLee, X.; Li, X.; Veldman, G.M.; Finnces serving as transcriptional and translational regulatorsrty, H.; Racie, L.; LaVallie, ^[12][13]E.; These sequences could be co-opted for newly integrated retroviral gene regulation.

Nevertheless,ang, X.Y.; Edouard, P.; Howes, S.; et al. Syncytin isolid a

confirmation of a ptive retrovirus integration into sperm or egg has not been obtained, and the mechanism of integration remains unclear. The rarity of such events owes in no small part to the nal envelope protein involved in human placental morphogenesis. Nature 2000, 403, 785–789

Nakagarrow windows of possibility for infection, but conversion to activea, S.; Bai, H.; Sakurai, T.; Nakaya, ERVsY.; is also cKontingent on the perfect confluence of criteria as follows:

  no, T.; Miyazawa), The insertion of.; Gojobori, T.; ERVs can Imake functionawal genes of the host placenta-specific.

 , K. Dynamic      i.e., Fematirn-1 integrativon inluto the intron 18 ion of pr

egnancy specific FAT2 dogene.

  b) Its own LTR ius sufficient to transcribe its gene segments, which serves as the cis-acting element(s), resulting in the activation of a host gene.

 retrovirus-derived genes expressed in bovine conceptuses during the period of placentation. Genome      Bi.e.ol. Evol. 2013, IFNG

5, THE1B on CRH. 296–306.

 Ono, c) It can make use of transcription factors utilized by the pre-existing gene, as per the baton-pass hypothesis.

 R.; Kobayashi, S.; Wagatsuma, H.; Aisaka, K.; Kohda, T.; Kaneko-Ishino, T.; Ishino,    iF.e., A transcription factor GCM1 for syncytin-1 a A retrotransposon-d syncytin-2.

  d) The ERV ris co-optved alonggene,

PEG10, with its promoter/enhancer in the integrated genome.

 s a novel imprinted gene    i.locate., Syncytin post-transcriptional regulatory element (SPRE)d on human chromosome 7q21.

  Ge) There is cooperation with miRNAs anomics 2001, 73, 232–237.

Ond/or lncRNAs, yet not definitely characterized under placental/trophectodermal conditions, either alone or together with         ERV

It , R.; Nakamura, K.; Inoue, K.; Naruse, M.; Usami, T.; Wakisaka-Saito, N.; Hino, T.; Suzuki-Migishima, R.; Ogonuki, N.;

Mikis, now clear that the emergence of mammalian placentas was made possible with thH.; et al. Deletion of Peg10, an imprinted gene acquisition of therianred from PEG10 and eutherian PEG11/RTL1 generetrotrans, fpollowed by independent, yet successive integrations of syncytin-son, causes early embryonic lethalitype. ERV gNat.

Genest. 2006, 38, 101–106.

Strucekitural variations in mammalian placentas could have been obtained througha, Y.; Wagatsuma, H.; Nakamura, K.; Ono, R.; Kagami, M.; Wakisaka, N.; Hino, ERVs’ownT.; fSuzunctions as well as the reki-Migishima, R.; Kohda, T.;

Ogulration of functional genes and/or ERVs themse, A.; et al. Rolves. A question still arises as to whether the placental structures that we know now are the ultimate forms or are still evolving. If the latter is the case, of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placental structures may still b. Nat.

Ge diversifying and new variations could be awaiting discoveryet. 2008, 40, 243–248.