Placentas are most diverse organs across mammalian species. Although the mammals obtained several new genes specific to pregnancy recognition and/or maintenance, wthich are often species’ specific, gene expressions for placental development and/or their structural diversity have not been well characterizede diversity of placental structures cannot be explained through the expression and functions of functional genes. It has long been thought that viral/transposon 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 (Baba et ^[2][3][4]al., 2011; Dewannieux & Heidmann, 2013; Cornelis et al., 2013), but none of them contain the same nucleotide structures, strongly suggesting that these ERVs are independently captured and integrated into mammalian genomes ^[5](Nakagawa et al., 2013).

MaImmalian placentas are extraordinarily diverse in terms of cell types, structure and their association with maternal blood, although placentas play the same roles such as physical and immunological protection against the maternal immune system, nutrient and gas exchanges, and endocrinological regulation ^[6]. Dprinting genes such as those of paternally expressed genes PEG10 (Ono et al., 2001) and PEG11/RTL1 (Charlier et al., 2001) have been extensively studied and through gene ablation studies, these genes are found necessary for the formation of placental structuries (Ong the last several decades, scientists in developmental biology and/or virologists have occasionally proposed retrovirus’s role ino et al., 2006; Sekita et al., 2008). Because PEG10 is acquired more than 146 million years ago, PEG10 gene could explain the initial formation of placental evolution. For example, Haig (2012) proposed that thes in mammals. However, placenta became a mammalian tissue in which retroviral genes were domesticated to serve an adaptive function in the hostl diversity cannot be explained. In this review, we have presented recent and related findings that explain how syncytin ^[7].genes Suchare an interplay may have contributed to evolutionally mechanisms associated with genomic imprinting of numerous genes.

Figure legend: Minvolved in placental diversity. We also presented recent observations on ERVs and how these ERVs control gene expression of both functionammalian placentas as classified by the distribution of chorionic villi. genes as well as ERV themselves (Chuong, 2018; Kitao et al., A:2021). DiffuBase placentas to which pigs and horses belong. B: Cod on the recent information, we have presented the batyledonary placentas, commonly found in ruminant ungulates.-pass hypothesis, successive integration of ERVs C: Zon(Imary plkacentas to which dogs and cats belong. D: Diwa et al., 2015) and new modelscoid placentas, seen in murine and primate species including humansexplaining placental diversity.

Imprinting Fusogenes such as those of paternally expressed genes, PEG10 ^[8] ic activity in the mammaliand PEG11/RTL1 ^[9], trophave been extensively studied for their contribution to the evolutional development of mammalianctoderm exhibits a great deal of similarity across species. Through gene ablation studies, these genes are found necessary for the formation of , notwithstanding the huge diversity in placental structures ^[10][11].and Btypecause PEG10 is acquired more than 146 million years ago, of placentation such as invasive (humans and murine) or PEG10 gene could explain the initial formation of placentas in mammals. However, structural diversity of placentas cannot be explained through the integration and n-invasive (ruminants). Based on actual experimentation and typical amino acid sequences, their function of PEG10 s and PEG11/RTL1re genes.rally The phylogenetic record shows multiple independent instances oflimited to fusogenic activity and immunotolerance, which on syncytin-typheir ERVown garenes’ entry into disparate clades ov not sufficient to fully explain the structural diversity of placentas.

Dunn-Fler the last 50 million years ^[5], scher and colleagues (2018) have demonstrated that retrongviraly THE1B sequggesting that syncytin-typence gsenrves as prime candidatesa cis-element for the emergence of structural diversification ofregulation of corticotropin-releasing hormone (CRH) mammaliagen placentase expression. Recently, more and more dataprogress has been made on research into haveERV bseen accumulated, demonstrating thatquences serving as transcriptional and translational syncytin-regulatype ERVors control gene expression of both function(Chuong 2018; Kitao et al., 2021). These sequences could be co-opted for newly integrated retroviral genes as well as ERV regulation.

Neverthemselvesess, ^[12][13]. It solisd often observed that ERV confirmation of a retrovirus integrations into mammalian genomes proceed successively: onsperm or egg has not been obtained, and the ERV mexaptchanism of integration is followed by successive invasions of new ERVremains unclear. The rarity of such events owes. The new interloper retroviral genes may subsume the role previouin no small part to the narrow windows ERVsof possibilayed. These ongoing and successity for infection, but conversion to active ERVs acquisitions for the establishment of more advantageous systems are explained by “a baton pass hypothesis” ^[14].is also contingent on the perfect confluence of criteria as follows:

1. The insertion of ERVs can make functional genes of the host placenta-specific. i.e., Fematirn-1 integration into the intron 18 of pregnancy specific FAT2
2. Its own LTR is sufficient to transcribe its own gene segments, which serves as the cis-acting element(s), resulting in the activation of a host gene. i.e., IFNG, THE1B on CRH.
3. It can make use of transcription factors utilized by the pre-existing gene, as per the baton-pass hypothesis. i.e., A transcription factor GCM1 for syncytin-1 and syncytin-2.
4. The ERV is co-opted along with its promoter/enhancer in the integrated genome; i.e., SPRE (syncytin post-transcriptional regulatory element).
5. There is cooperation with miRNAs and/or lncRNAs, yet not definitely characterized under placental/trophectodermal conditions, either alone or together with ERV

In general, the placentas have lower DNA methylation levels than embryos, allowing freer expression of ERVs and transposons during gestation, thereby facilitating selection of advantageous genes from a wider market. Such extraembryonic circumstances might have allowed for not only domestication of ERVs to establish novel endogenous genes via multiple of selections but also the dissemination of ERVs and transposons throughout genomes as transcriptional regulators. Moreover, ERVs could serve as cis- and/or trans-acting factors for functional genes of the host. Similarly, various degrees of maternal-fetal cell interactions in the uterine compartment may have led to change in kinds and degree of gene usage ^[7](Haig 2012), possibly resulting in cellular and morphological changes in placentas. It is interesting to speculate that the placentas themselves might have served as an evolutionary laboratory to promote mammalian evolution (Kaneko-Ishino & ^[15]Ishino, 2015).

TheIt outer most cell layer is now clear that the fetal side of emergence of mammalian placentas is called “trophectoderm”.was made possible with the acquisition of therian AcrossPEG10 mammalnd eutherian spPEG11/RTL1 gecines, the trophectodermal cells exhibit a great deal followed by independent, yet successive integrations of fusosyncytin-type genices for activity, notwithstanding the huge diversity instructural variations. A question still arises as to whether the placental structures and type of placentation such as invasive (humans and murine) or non-invasive (pigs and ruminants) to the maternal endometrium. that we know now are the ultimate forms or are still evolving. If the latter is the case, placental structures may still be diversifying and new variations could be awaiting discovery

Related refences

Basedba, on actual experimentation and typical amino acid sequences, ERVs’ K.; Nakaya, Y.; Shojima, T.; Muroi, Y.; Kizaki, K.; Hashizume, K.; Imakawa, K.; Miyazawa, T. Identifunictions are generally limited to fusogenic activity and immunotoleranceation of novel endogenous betaretroviruses which are transcribed in the bovine placenta. J. Virol. 2011, w85, 1237–1245.

Charlich on their own are not sufficient to fully explain the structural diversity of placentas.

Duer, C.; Segers, K.; Wagenaar, D.; Karim, L.; Berghmans, S.; Jaillon, O.; Shay, T.; Weissenbach, J.; Cockett, N.; Gyapay, G.; et al. Human-ovine comparative sequencing of a 250-kb imprinted domain encompassinn-Fleg tcher and colleagues (2018) have demonstrated that retroviralhe callipyge (clpg) locus and identification of six imprinted transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8. Genome. Res. 2001, THE1B11, seq850–862.

Chueonce serves as a cis-element for the regulation of corticotropin-releasing hormone (CRH) g, E.B. The placenta goes viral: Retroviruses control gene expression ^[16].in Rprecentlygnancy. PLoS Biol. 2018, pr16, e3000028.

Cogress has been made on research intonelis, G.; Heidmann, O.; Degrelle, S.A.; Vernochet, C.; Lavialle, ERVC.; sLequences serving as transcriptional and translational regulatorstzelter, C.; Bernard-Stoecklin, S.; Hassanin, A.; Mulot, ^[12][13]B.; These sequences could be co-opted for newly integratGuillomot, M.; et al. Captured retroviral gene regulation.

Nenvelope syncytin genev associatertheless, solid confirmatd with the unique placental structure of higher ruminants. Proc. Natl. Acad. Sci. USA 2013, 110, E828–E837.

Dewannieux, M.; Heidmann, T. Endon of a genous retrovirus integres: Acquisition, amplification into sperm or egg has not been obtainedand taming of genome invaders. Curr. Opin. Virol. 2013, 3, a646–656.

Dunnd -Flethe mechanism of integration remains unclear. The rarity of such events owes in no small part to the narrow windows of possibility for infection, but conversion to active ERVcher, C.E.; Muglia, L.M.; Pavlicev, M.; Wolf, G.; Sun, M.A.; Hu, Y.C.; Huffman, E.; Tumukuntala, S.; Thiele, K.; Mukherjee, A.; et al. Anthropoid primate-specific retroviral element THE1B controls expression of CRH in placenta and alters iges also conttation length. PLoS Biol. 2018, 16, e2006337.

Haingent on, D. Retroviruses and the perfectlacenta. confluenceCurr Biol 2012, 22, R609-613.

Imakawa, K.; Nakagawa, ofS.; criteria as followMiyazawa, T. Baton pass hypothesis:

  a) ThSuccessive insercorporation of ERVunconserved can make functionendogenous retroviral genes of the hostfor placenta-specific.

 tion during  mammalian    i.e.,evolution. FGematirn-1nes iCells 2015, 20, 771–788.

Kantegration into the intron 18 of pregnancy ko-Ishino, T.; Ishino, F. Mammalian-specific FAT2 gene.

  b) Its own LTR mis sufficient to transcribe c functions: Newly acquired traits gene segments, which serves as the cis-acting element(s), resulting in the activation of a host gene.

 erated by genomic imprinting and LTR retrotransposon-derived genes  in  mammals.  i.e.,Proc. Jpn Acad. IFNG,Ser. THE1B on CRH Phys. Biol. Sci.

  2015, c)91, I511-538.

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

 K.; Nakagawa, S.; Miyazawa, T. An ancient retroviral RNA element hidden in mammalian genomes and its involvement in co-opted    i.re., A transcriptiontroviral gene regulation. factorRetrovirology GCM2021 for, 18, syncytin-1 and syncytin-2.36.

 Mi, d) TheS.; Lee, ERVX.; Lis co-opted along with its promoter/enhancer in the integrated genome, X.; Veldman, G.M.; Finnerty, H.; Racie, L.; LaVallie, E.; Tang, X.Y.; Edouard, P.; Howes, S.

 ;  et  i.e.,al. Syncytin post-transcriptional regulatory element (SPRE).

  is a captive retroviral enve) Thlopere is cooperation with miRNAs and/or lncRNAs, yet not definitely characterized under protein involved in human placental/trophectode morphogenesis. Nature 2000, 403, 785–789.

Nakagawa, S.; Bai, H.; Sakurmai, T.; Nakayal conditions, either alone or together with         ERV

It , Y.; Konno, T.; Miyazawa, T.; Gojobori, T.; Imakawa, K. Dynamic evolution of endogenous retrovirus-derived genes expressed in bovisne now clear that the emergence of mammalian conceptuses during the period of placentation. Genome Biol. Evol. 2013, 5, 296–306.

Ono, R.; Kobayas was made possible with the acquisition of therianhi, S.; Wagatsuma, H.; Aisaka, K.; Kohda, T.; Kaneko-Ishino, T.; Ishino, PEG10F. andA eutherian PEG11/RTL1 generetrotrans, fpollowed by independent, yet successive integrations ofson-derived gene, PEG10, is a novel imprinted gene located on human chromosome 7q21. syGencytin-typeomics 2001, ERV73, ge232–237.

Oneso, R. Structural variations in mammalian placentas could have been obtained through; Nakamura, K.; Inoue, K.; Naruse, M.; Usami, T.; Wakisaka-Saito, N.; Hino, T.; Suzuki-Migishima, R.; ERVs’Ogown functions as well as the regulauki, N.; Miki, H.; et al. Deletion of functional genes and/or ERVs thePeg10, an imprinted gene acquired fromselves. A question still arises as to whethera retrotransposon, causes early embryonic lethality. Nat. Genet. 2006, the38, plac101–106.

Senkital structures that we know now are the ultimate forms or are still evolving. If the latter is the case, placental structures may still be diversifying and new variations could be awaiting, Y.; Wagatsuma, H.; Nakamura, K.; Ono, R.; Kagami, M.; Wakisaka, N.; Hino, T.; Suzuki-Migishima, R.; Kohda, T.; Ogura, A.; et al. Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta. Nat. Genet. 2008, 40, discovery243–248.