From ancestral infectious retroviruses to bona fide cellular genes:
Role of the captured syncytins in placentation
A. Dupressoira,b,1, C. Laviallea,b,1, T. Heidmanna,b,*
aUnité des Rétrovirus Endogènes et Éléments Rétroïdes des Eucaryotes Supérieurs, CNRS, UMR 8122, Institut Gustave Roussy, 114 rue Édouard Vaillant, 94805 Villejuif, France
bUniversité Paris-Sud, 91405 Orsay, France
a r t i c l e i n f o
Accepted 16 May 2012
a b s t r a c t
During their replication, infectious retroviruses insert a reverse-transcribed cDNA copy of their genome,
a “provirus”, into the genome of their host. If the infected cell belongs to the germline, the integrated
provirus can become “fixed” within the host genome as an endogenous retrovirus and be transmitted
vertically to the progeny in a Mendelian fashion. Based on the numerous proviral sequences that are
recovered within the genomic DNA of vertebrates e up to ten percent in the case of mammals e such
events must have occurred repeatedly during the course of millions of years of evolution. Although most
of the ancient proviral sequences have been disrupted, a few “endogenized” retroviral genes are
conserved and still encode functional proteins. In this review, we focus on the recent discovery of genes
derived from the envelope glycoprotein-encoding (env) genes of endogenous retroviruses that have been
domesticated by mammals to carry out an essential function in placental development. They were called
syncytins based on the membrane fusogenic capacity that they have kept from their parental env gene
and which contributes to the formation of the placental fused cell layer called the syncytiotrophoblast, at
the maternoefetal interface. Remarkably, the capture of syncytin or syncytin-like genes, sometimes as
pairs, was found to have occurred independently from different endogenous retroviruses in diverse
mammalian lineages such as primates e including humans e, muroids, leporids, carnivores, caviids, and
ovis, between around 10 and 85 million years ago. Knocking out one or both mouse syncytin-A and -B
genes provided evidence that they indeed play a critical role in placentation. We discuss the possi-
bility that the immunosuppressive domain embedded within retroviral envelope glycoproteins and
conserved in syncytin proteins, may be involved in the tolerance of the fetus by the maternal immune
system. Finally, we speculate that the capture of a founding syncytin-like gene could have been instru-
mental in the dramatic transition from egg-laying to placental mammals.
? 2012 Elsevier Ltd. All rights reserved.
During the course of evolution, vertebrates have been exposed
to multiple waves of infection by retroviruses. Taking advantage of
their remarkable capacity to insert their DNA into the genome of
target cells, some retroviruses have integrated into the germline of
their host. They were then inherited vertically from one generation
to the next in a Mendelian fashion (Fig. 1). As a consequence of
numerous amplification events, endogenous retroviruses (ERVs)
now compose multigene families and occupy a substantial fraction
of the genome of vertebrates (8e10% in humans and mice) [1,2]. In
their overwhelming majority, these so-called “proviruses”, not
being subject to any selective pressure, have progressively become
disabled by simple accumulation of mutations or deletions. As
a result, among all the copies of a given ERV family, only a few
elements may still be infectious in some host species, namely those
that have been recently “endogenized” into the genome of their
host and that are still able to replicate and integrate new proviral
copies within the germline; this is for instance the case for the
koala retrovirus (KoRV) , the mouse leukemiaviruses (MLVs) and
the mouse mammary tumor virus (MMTV) , or the endogenous
jaagsiekte sheep retrovirus (enJSRV) . In other rare cases, only
some of the retroviral genes were preserved and have remained
functional over several millions of years following ERV integration,
whereas all other retroviral genes of the same age had degenerated
* Corresponding author. Unité des Rétrovirus Endogènes et Éléments Rétroïdes
des Eucaryotes Supérieurs, CNRS, UMR 8122, Institut Gustave Roussy, 114 rue
Édouard Vaillant, 94805 Villejuif, France. Tel.: þ33 1 42 11 49 70; fax: þ33 1 42 11
E-mail address: email@example.com (T. Heidmann).
1These authors (A.D. & C.L.) equally contributed to this review article.
Contents lists available at SciVerse ScienceDirect
journal homepage: www.elsevier.com/locate/placenta
0143-4004/$ e see front matter ? 2012 Elsevier Ltd. All rights reserved.
Placenta 33 (2012) 663e671
or had been lost. Conservation of ERV genes through evolution is
highly suggestive of a selection pressure exerted by the host due to
beneficial effects provided by such genes. A striking example of
such a positive selection process is provided by the functional
“capture” of viral env genes. Indeed, these genes, which encode the
envelope glycoprotein of retroviruses, were found to have been
selected in eutherian mammals for a key physiological role in
placenta formation (Fig. 1).
2. Pleiotropic role of the retroviral envelope protein: from
the virus replication cycle to a cellular biological function
The envelope protein of retroviruses plays a critical role for
entry of the viral particles into target cells during the infectious
cycle . This protein is composed of two subunits assembled at the
surface of infected cells and transferred to the virion during its
budding at the plasma membrane (Fig. 2A). In the course of infec-
tion, the surface subunit (SU) positioned on the outside of the
virion binds to a specific cellular receptor on the surface of the
target cell. The virion-anchored transmembrane subunit (TM)
triggers the fusion of the viral membrane with the plasma
membrane of the target cells thanks to a fusion peptide (Fig. 2A, B)
and the viral nucleocapsid is then released into the cytoplasm . A
few “endogenized” ERV env genes encode envelope glycoproteins
that have kept some of the properties of the cognate proteins
initially encoded by their ancestral infectious viruses, such as
binding to a cell receptor, with decisive physiological consequences
for the cells and the organisms where they are expressed. For
instance, the retroviral env-derived murine genes, Fv4 (Friend virus
susceptibility 4) and Rmcf (resistance to MCF virus), and the ovine
endogenous enJSRV ERV env genes confer resistance to infection by
exogenous retroviruses by interfering with their receptors and
limiting the availability of the latter at the surface of the cell
membrane [5,7]. Moreover, in the same way as infection by some
viruses e such as Human Immunodeficiency Virus (HIV) or measles
virus e can drive the fusion of infected cell membranes , enve-
lope proteins from ERVs expressed at the cell surface can induce
fusion with a neighboring cell provided that the latter displays the
appropriate receptor on its own surface. Such fusion can involve
several adjoining cells leading to the formation of a multinucleated
giant cell, designated a syncytium (Fig. 2B). Genes encoding fuso-
genic envelope proteins were identified for the first time within the
human genome among members of the human endogenous
retrovirus (HERV) families [9e11].
3. Occurrence of envelope protein-coding genes within the
Exhaustive search within the human genome for env genes with
long open reading frames (ORFs) disclosed only 18 genes encoding
a putative envelope protein [12,13]. Among those potentially
endowed with a function, the first to be described was the ERV3
protein, which is specifically expressed in the placenta and is
encoded by a proviral gene conserved in the Hominid and Old
Fig. 1. Mechanism of retroviral endogenization. Retroviruses have the capacity to reverse transcribe their genomic RNA into a DNA copy which is then inserted into the genome of
infected cells in the form of a provirus harboring the 3 viral genes gag, pol, and env (left). Retroviral infection of individuals leads to integration of the viral genome into a limited
number of cells of the organism. Production of new infectious virions allows the horizontal transmission of infection, from one individual to the next (top right). In the rare cases
where a retrovirus infects cells from the germline of its host, the integrated viral genome is transmitted to the progeny (center). The retrovirus has become endogenous and is
present in all cells of the individual. During the course of evolution, most proviral genes are disrupted by multiple mutagenic events but occasionally one of them, such as the env
gene exemplified here (bottom left), may be preserved and remains functional over several million years, contributing to the physiology of its host.
A. Dupressoir et al. / Placenta 33 (2012) 663e671
World Monkey families . The ERV3 protein lacks a hydrophobic
membrane spanning domain and therefore the capacity to function
as a fusogenic protein, and was suggested to play a role in
However, the finding of a premature stop codon in a homozygous
state in 1% of the human population and the absence of the ERV3
gene in the gorilla  ruled out the possibility that this otherwise
highly conserved gene is essential for survival or reproduction .
Alternatively, in humans, the ERV3 genemay presently be subject to
a process of progressive loss of function due to compensatory
functional replacement by another gene(s). Attention was then
drawn to two envelope glycoproteins, encoded by a member of
either the HERV-W [9,10] or the HERV-FRD family . Both env
genes are specifically expressed in the placenta and, when intro-
duced into cultured cells, drive syncytium formation (Fig. 2B),
which led to their designation as syncytin-1 and syncytin-2,
respectively (Table 1). Each protein binds a distinct receptor:
syncytin-1 interacts with the RD114/simian type D retrovirus
receptor [RDR, also designated ASCT-2; official gene nomenclature,
SLC1A5 for solute carrier family 1 (neutral amino acid transporter),
member 5]  and syncytin-2 with a transmembrane protein,
encoded by the major facilitator superfamily domain containing 2A
gene (MFSD2A, originally MFSD2) . Comparative analysis of the
genomes from various species revealed that the syncytin-1 gene is
present in the genomeof primates since the separation of Hominids
fromOld World monkeys,i.e. around 25 millionyears (My) ago.
Syncytin-2 is older, being conserved in the genome of all monkeys,
than 40 My (Fig.3A).
Compellingly, the very low rate of polymorphism of both genes
within the human population argues in favor of an essential
physiological function . Several features of both encoded
envelope proteins led to formulate the hypothesis that they
contribute to the formation of an essential component of the
placenta, i.e. the syncytiotrophoblast.
4. Development of the human placenta
The placenta is an autonomous and transient organ of embry-
onic origin whose primary function is to achieve reciprocal meta-
bolic exchanges between the fetus and its mother. It is also a site of
immune tolerance ensuring the preservation of the fetus, which
harbors “foreign” paternal antigens, within its mother’s body. The
placental tissue, namely the trophoblast, stems from peripheral
cells of the blastocyst, the cytotrophoblasts. The latter are among
the rare cells of the human body, together with the myoblasts, the
macrophages and the oocytes and spermatozoids, endowed with
the capacity of cellecell fusion. Beginning at the 6th embryonic day
(E6), cytotrophoblasts fuse together to form a multinucleated
syncytial layer, designated the syncytiotrophoblast, which is highly
invasive and allows implantation of the embryo into the uterine
endometrium . From E15, the genuine functional units of the
placenta, the chorionic villi, start to develop. They are crisscrossed
with fetal blood vessels and either float freely in the intervillous
maternal blood spaces or are anchored into the uterine wall
(Fig. 3B). At this stage, the syncytiotrophoblast covers the outside
surface of the floating villi. It is continuously regenerated and
Fig. 2. Structure and function of retroviral envelope proteins, and properties of human syncytin-1 and -2. (A) Structure of the envelope glycoproteins of retroviruses. The surface
(SU) subunit contains a receptor binding domain (RBD) and the transmembrane (TM) subunit harbors a fusion peptide, an immunosuppressive domain (ISD) and a transmembrane
anchoring domain (left). Following cleavage, the SU and TM remain associated (right). Upon binding of the SU to its receptor, the fusion peptide at the N-terminus of the TM drives
the fusion of the membrane where it is anchored with the plasma membrane of the target cell bearing the SU receptor. (B) Consequences of the interaction between a retroviral
envelope protein and its cognate receptor: fusion of the virion membranous envelope with the target cell membrane allows entry of the virion into the infected cell (left panel) or
fusion between the membranes of adjoining cells results in formation of a syncytium (middle panel). Transfection of human TE671 cells with syncytin-1 or syncytin-2 induces
cellecell fusion and formation of multinucleated syncytia (right; May-Grünwald-Giemsa staining).
A. Dupressoir et al. / Placenta 33 (2012) 663e671
expands by fusion with underlying cytotrophoblasts. The initial
notion that parts of the normal syncytiotrophoblast are discarded
by apoptosis, being “deported” into maternal blood under the form
of so-called “syncytial knots” or “syncytial sprouts” has been
recentlychallenged . This essential tissue, in direct contact with
maternal blood, plays diverse roles ranging from exchange func-
tions (O2, CO2, nutrients, etc.) between mother and fetus, secretion
of steroid hormones and human chorionic gonadotropin (hCG),
regulation of the immune response or even protection against
potential pathogens . Lastly, the so-called extravillous cyto-
trophoblasts that originate from an independent differentiation
pathwayand are located at the base of the anchoring villi acquirean
invasive phenotype that leads them to migrate into the uterine
decidua where they differentiate into giant cells. They also pene-
trate inside the uterine “spiral arteries” where they gradually
replace the endothelial cells leading to their remodeling into low
resistance vessels and thus increasing the maternal blood supply to
the fetus (Fig. 3B) .
Syncytin genes identified in mammals.
Name Accession number (species)Locus Size
Conservation Expression siteReceptorRefs
AF208161 Homo sapiens
>25 My hominoidsevery trophoblast cell typesASCT-2Mi et al., 2000 ,
Blond et al., 2000 
Blaise et al., 2003 
Dupressoir et al., 2005 
Dupressoir et al., 2005 
Heidmann et al., 2009 
NM_207582 Homo sapiens
AY849973 Mus musculus
AY849977 Mus musculus
JN587092 Canis familiaris
>65 My carnivoressyncytiotrophoblastn.d.a
Cornelis et al., 2012 
an.d., not determined.
Fig. 3. Syncytins in humans. (A) Phylogenetic tree of primates. Arrows indicate the time of insertion into the genome of primates of the two retroviruses that have bequeathed the
syncytin-1 and -2 genes. (B) Schematic representation of a human placental villus. (C) Immunohistochemical staining of human placental villous sections for syncytin-1 showing
that it is expressed in all types of trophoblast cells. From Malassiné et al., 2010 . (D) Left panel: Immunohistochemical staining and in situ hybridization of human placental
villous sections for syncytin-2 and MFSD2 expression, respectively. MFSD2 expression is restricted to the syncytiotrophoblast layer (ST), while syncytin-2 expression is restricted to
underlying mononucleated cytotrophoblasts (CT) From Esnault et al., 2008  and Malassiné et al., 2007 , respectively. Right panel: "In fusion" model for syncytiotrophoblast
formation, where interaction between syncytin-2 and MFSD2 drives polarized fusion of the cytotrophoblast into the syncytiotrophoblast.
A. Dupressoir et al. / Placenta 33 (2012) 663e671
5. Involvement of syncytins in human placental development
In situ investigation of the sites of syncytin gene expression
within placental tissues first suggested that they were involved in
placental development. Syncytin-1 is rather broadly expressed
throughout the placenta in all the villous cytotrophoblast, syncy-
tiotrophoblast and extravillous cytotrophoblast lineages (Fig. 3C)
[23,24]. Interestingly, the placenta-specific transcription factor
Glial-Cell Missing 1 (GCM1; also known as GCMa) was shown to
regulate syncytin-1 expression and to exhibit an overlapping
expression profile with syncytin-1 in placental tissues . At this
time, there is no neat consensus as to the localization of the
expression sites for the RDR/ASCT-2 syncytin-1 receptor in
trophoblastic cells, which seems to depend on the nature of the
antibodies used, so that a clear picture of syncytin-1 involvement in
syncytiotrophoblast formation cannot be drawn. In contrast, syn-
cytin-2 expression is detected in only a fraction of the villous
cytotrophoblasts , whereas the gene encoding its receptor,
MFSD2A, is found to be expressed in the syncytiotrophoblast
(Fig. 3D) . Highly regulated expression of both syncytin-2 and
MFSD2A in distinct cell types may allow incorporation by fusion of
mononucleated cytotrophoblasts into the contiguous syncytio-
trophoblast, while precluding fusion of the cytotrophoblasts
between themselves. This process of polarized “in-fusion” may
favor growth and renewal of the syncytial tissue throughout
pregnancy (Fig. 3D) . In models of primary cultures of cyto-
trophoblasts that spontaneously differentiate, extinction of syncy-
tin-2 and, toa lesserextent, thatof syncytin-1, either bythe addition
of antisense oligonucleotides or by RNA interference with small
inhibitory RNAs (siRNAs), greatly decreases fusion efficiency
together with the associated production of hCG [27,28]. Altogether,
these data argue for a major role of syncytin-2 (likely acting in
synergy with syncytin-1) for the differentiation of cytotrophoblasts
into syncytiotrophoblast. Although other factors were previously
identified in vitro as being involved in the fusion process (e.g.,
phosphatidylserine externalization, the connexin 43-, cadherin 11-
and CD 98-encoding genes, the zona occludens-1 (ZO-1) gene)
[29,30], the true effectors are undoubtedly the syncytin genes,
owing to their fusogenic properties. It has to be stressed that there
are no data on the possible involvement of syncytins in formation of
the invasive syncytiotrophoblast at early implantation stages, due
to the limited availability of such a material at these stages in
humans. Besides syncytins, another envelope protein gene,
belonging to a provirus from the HERV-V family, is also specifically
expressed within human placenta but its putative role in placen-
tation remains to be investigated .
Hypotheses have been raised that some pregnancy diseases e
such as preeclampsia, intrauterine growth retardation, some cases
of early embryonic death, anomalous placentae from trisomy 21-
affected fetuses, or even choriocarcinoma e could originate from
defective syncytiotrophoblast formation or extravillous invasion
due to altered expression of one of the syncytin genes. Reports of
investigations carried out on diseased placentae have described
alterations of the expression of either one or the other syncytin
gene [32e34], but without providing definitive evidence for a cau-
seeeffect relationship. Further studies are required to firmly
establish such a correlation, for instance by identifying functionally
disruptive germline mutations within a syncytin gene associated
with a defined gestational disease.
6. Discovery of syncytin genes in the mouse: unequivocal role
With the aim of establishing an animal model to investigate the
role of syncytin proteins in placental development, syncytin-
encoding genes have been searched for in the mouse genome.
Remarkably, screening of the fully sequenced mouse genome led to
the identification of two genes encoding retroviral envelope
proteins, designated syncytin-A and -B, distinct from the human
syncytin-1 and -2 genes, but sharing the same characteristics :
they are specifically expressed in the placenta, are endowed with
fusogenic properties, and have been conserved since their inte-
gration into the genome of an ancestor of the muroids (rat, mouse,
hamster, vole and gerbil) more than 25 My ago (Table 1). In the
mouse placenta two distinct layers of syncytiotrophoblast (ST-I and
ST-II) separate the fetal capillaries from the maternal blood lacunae
(Fig. 4). Although the mouse and human placentae differ in the
details of their gross architecture, it has been proposed that
a functional analogy could be made between the murine ST-I and
ST-II layers and the single syncytiotrophoblast layer of the human
placenta: the two murine layers could be thought of as one struc-
ture because they are closely apposed with gap junctions allowing
direct communication between their respective cytoplasms (for
general reviews providing an in-depth comparison between the
mouse and human placentae, see Georgiades et al., 2002  and
Watson and Cross, 2005 ). The syncytin-A gene was shown to be
expressed in the ST-I layer (Fig. 4), which is the closest to maternal
blood, whereas syncytin-B expression was detected in the ST-II
layer, closer to fetal blood vessels . Akin to human syncytin-1,
syncytin-B expression is regulated by the mouse Gcm1 transcrip-
tion factor, in agreement with the co-expression of both the syn-
cytin-B and Gcm1 genes in the ST-II layer. Loss of the syncytin-A
gene in knockout mice had dramatic effects, since mouse embryos
homozygous for the deletion died in utero at mid-gestation .
Early placental architecture was found to be disrupted with an
accumulation of unfused cytotrophoblasts and defective syncyti-
alization of the ST-I layer (Fig. 4). In contrast, knocking out the
syncytin-B gene had only mild effects, since syncytin-B null mouse
embryos were viable showing only limited late-onset growth
retardation and a slight, although significant, decrease in neonate
numbers . The syncytin-B null mutant placenta displayed
impaired formation of the ST-II layer with evidence of unfused,
apposed cells and enlarged maternal blood spaces, leading to
alterations in placental structure (Fig. 4). Analysis of its tran-
scriptome, compared to that of wild type placenta, showed induc-
tion of the expression of the gene encoding the gap junction
protein, connexin-30, which was furthermore found to accumulate
at the maternoefetal interface in the area of the unfused ST-II cell
layer. These results suggested the occurrence of compensatory
mechanisms mediated by gap junctions, known to be involved in
cellecell communications, which would counteract the fusion
defects, thus allowing embryos lacking the syncytin-B gene to
survive. Remarkably, double knockout mouse embryos lacking both
the syncytin-A and -B genes displayed a more deleterious pheno-
type than did the syncytin-A single knockout embryos, since they
died earlier . Thus, both syncytial layers, ST-I and ST-II coop-
erate to maintain the structural and functional integrity of the
maternoefetal interface. The study of these mice provided the first
demonstration of the critical role played by syncytin genes in
placenta development. They also constitute a model to investigate
the involvement of these genes in placental diseases associated
with fusion defects.
7. Syncytins in other mammals
Although they share similar properties, the primate and muroid
syncytin genes are clearly not orthologous e they do not belong
to syntenic chromosomal regions between the two groups of
species e indicating that they result from independent events of
gene capture having occurred separately in the genome of
A. Dupressoir et al. / Placenta 33 (2012) 663e671
ancestors of each lineage (Table 1). Along this line, a fifth syncytin
gene, syncytin-Ory1, distinct from the four previous ones, has been
identified in a third mammalian lineage, namely in the Leporidae
family (rabbit, hare) . The syncytin-Ory1 gene encodes a fuso-
genic, placenta-specific envelope protein and has been conserved
for more than 12 My. It shares the same receptor, RDR/ASCT-2/
SLC1A5, as the human syncytin-1 protein. Syncytin-Ory1 was
found to be expressed in the placenta junctional zone, where the
invading syncytial tissue contacts the maternal decidua, suggesting
its possible contribution to the formation of the syncytiotropho-
blast. Recently, a new functional syncytin gene, syncytin-Car1, was
identified in 26 species of carnivores  that belong to the Laur-
asiatheria super order, which diverged from the Euarchontoglires
(to which pertain the lineages investigated up to now: primates,
rodents and lagomorphs) more than 100 My ago. This makes syn-
cytin-Car1 the oldest syncytin gene identified to date. In both dog
and cat, syncytin-Car1 is fusogenic and specifically expressed in the
placenta at the level of the syncytiotrophoblast layer within the
Altogether, these studies unambiguously demonstrate that the
co-optation of retroviral env genes has occurred independently and
on multiple occasions during mammalian evolution (Table 1, Fig. 5)
and may have thus contributed repeatedly to the emergence of
a syncytial placental interface, illustrating a remarkable phenom-
enon of evolutionary convergence. Although the rationale for
a syncytial structure is still an open question, one may argue that it
may be better suited for rapid and effective interstitial implanta-
tion, as well as for the establishment of a continuous maternoefetal
interface at later stages of placentation. Interestingly, comparative
anatomy reveals a wide diversity of placental structures between
mammalian species (reviewed in Wooding and Burton, 2008 ;
Fig. 5). Placentae mainly differ in the extent of invasion of the
maternal uterine tissues by the trophoblast covering the blastocyst
at the time of implantation and by the makeup of the resulting
maternoefetal interface. In the epitheliochorial placenta (horse,
pig), the fetal trophoblast, composed of unfused, noninvasive
cytotrophoblasts, is simply apposed as a monolayer to the intact
uterine epithelium. In the three other placental types, synepithe-
liochorial (ruminants), endotheliochorial (carnivores) and hemo-
chorial (humans,mice, rabbits), the fetal trophoblast becomes more
and more invasive from one type to the next, respectively, by dis-
carding more and more of the intervening maternal cell layers
(epithelial and endothelial cells), up to direct contact of the syn-
cytiotrophoblast with maternal blood in the case of the hemo-
chorial type (Fig. 5). However, the diverse placental structures are
not predictable simply on the basis of species taxonomy, and their
evolutionary pathways are still a matter of contention . In this
context, it will be of prime interest to investigate to what extent,
depending on fusogenic activity level, expression pattern, receptor
identity, etc., the syncytin genes captured by each species might
readily accountforthe observed
morphology and organization.
Finally, it has to be stressed that the contribution of exogenous
gene capture to placental morphogenesis is not limited to syncytin
genes sensu stricto. For instance, in the ewe, injection of antisense
morpholino-oligonucleotides in utero provided evidence that env
Fig. 4. Both syncytin-A and -B are required for the formation of the two-layered mouse placental syncytiotrophoblast. Upper: scheme of the mouse placenta (left) with a schematic
(middle) and electron microscopic (right) enlarged view of the fetoematernal interface showing the presence, in the mouse, of two syncytiotrophoblast layers (ST-I, ST-II) separating
the maternal and fetal blood spaces. Lower: electron microscopic analysis of the placental fetoematernal interface of normal mice (left) and of mice deficient for syncytin-A (middle)
or syncytin-B (right), showing fusion defects of syncytiotrophoblast layer ST-I and ST-II, respectively (Dupressoir et al., 2009 ; Dupressoir et al., 2011 ). Arrowheads in the
right panel point to electron-dense intercellular junctions.
A. Dupressoir et al. / Placenta 33 (2012) 663e671
genes from the enJSRV ERV family mentioned above are involved in
the regulation of placental growth and differentiation at the time of
implantation . Recently, another placenta-specific but non
fusogenic ERV env gene, designated env-Cav1, was identified within
the genome of the guinea pig , which is a member of a rodent
suborder distant from that to which the muroids belong. An
orthologous gene with a conserved open reading frame was found
to be present in all the individuals tested that are part of the Cav-
iomorpha rodent clade, consistent with a time of insertion >30 My.
Guinea-pig env-Cav1 is specifically expressed in the placenta at the
level of the so-called junctional zone that contains invasive cyto-
trophoblasts, suggesting a role in the invasion of the maternal
uterine tissues, as postulated for syncytin-1 in humans. No fuso-
genic activity of the env-Cav1-encoded protein could be demon-
strated, indicating that this gene may not play a role in placental
architecture, as that played by the previously identified classical
syncytins, but be involved in invasiveness and/or exert immuno-
suppressive functions (see below).
Of note, ERV env genes are not the only ones to have been
captured by mammals in the course of evolution. Other transpos-
able elements have also bequeathed to their ancestral host a gene
that has been domesticated for a function in placental growth. For
example, two genes, paternally expressed gene 10 (Peg10) and ret-
rotransposon-like 1 (Rtl1, also called Peg11), conserved in all
eutherian mammals, have been co-opted from suchi-ichi class, long
terminal repeat (LTR) retrotransposons (reviewed in Ref. ). Both
Peg10 and Rtl1/Peg11 were demonstrated to be essential for
mammalian placental development, at early and late stages,
respectively. Although the precise function and mechanism of
action of both genes remains to be elucidated, their discovery
provides furtherevidence that the captureof exogenous genes from
ancient retroelements has been a major innovating event in
8. Potential role of syncytin immunosuppressive activity in
The envelope protein of infectious retroviruses has been shown
to be endowed with an immunosuppressive function critical for
in vivo virus propagation . It turns out that syncytins have
conserved this property from their ancestral infectious progenitor,
since at least one of them, both in primates (syncytin-2) and in
muroids (syncytin-B) was shown to display immunosuppressive
activity, using in vivo assays based on the inhibition of tumor
rejection by the mouse immune system . The immunosup-
pressive activity is carried bya specific immunosuppressive domain
(ISD) within the TM subunitof the envelope protein (Fig. 2A) and an
amino acid crucial for this function has been identified at a specific
position within the ISD. This syncytin attribute may be involved in
maternal immune tolerance toward the allogeneic feto-placental
unit that expresses histo-incompatible paternal antigens. Actually,
this property could even be the primordial function of syncytins,
prior to their fusogenic capacity. Such a hypothesis can be experi-
mentally tested by generating genetically engineered mice that
Fig. 5. Multiple captures of syncytin genes across evolution and diversity of placental structures in mammals. We speculate that a founding event in the emergence of placental
mammals has been the capture of an ancestral retroviral env gene that was instrumental in conferring maternal tolerance toward the embryo through immune escape bestowed by
the immunosuppressive domain of the envelope glycoprotein, thus allowing development of a “primitive” placental tissue and close contact between mother and fetus (left).
Subsequent stochastic infections of the germline by (and endogenization of) distinct retroviruses would have led to the successive co-optation of new syncytin genes. The
phylogenetic tree of mammalian evolution shows the time of insertion of the six syncytin genes identified to date (middle). Roman figures indicate the four major eutherian clades:
Afrotheria (I), Xenarthra (II), Euarchontoglires (III) and Laurasiatheria (IV). At this time, syncytins have been identified in the Euarchontoglires (primates, muroids and leporids) and
Laurasiatheria (carnivores) classes. Capture of varied syncytins with differing properties and expression sites could explain the observed diversity of placenta organization among
mammalian species. The right panel shows a schematic representation of the maternoefetal interface in the four main types of placental structures. Placental types are classified in
order of increasing invasive properties and extent of syncytialization.
A. Dupressoir et al. / Placenta 33 (2012) 663e671
express a syncytin-B gene mutated so as to invalidate its immuno-
suppressive activity without altering its fusogenicity . But an
even bolder scenario can be envisioned, where emergence, more
than 150 My ago, of a primitive placenta in an oviparous vertebrate
gene that would have kept the immunosuppressive capacity of its
viral ancestor, thus allowing grafting of fetal tissues within the
mother’s body (Fig. 5). Such a founding env gene would have been
subsequently replaced in the diverse mammalian lineages upon
successive and independent germline infections by new retrovi-
ruses and co-optation of their env gene, assuming that each new
gene provides its host with a positive selective advantage. Nowa-
days, the accumulation of genomic sequences from an ever
increasing number of species offers multiple opportunities to
contributed to placental diversification and mammalian evolution.
Workcarried out in the laboratoryof the authors is supported by
the Centre National de la Recherche Scientifique and the Ligue
Nationale contre le Cancer (Équipe “labellisée”). We thank our
colleagues involved in the studies described in this review and
apologize to those investigators whose work in the field could not
be described or referenced here because of space limitations.
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