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REPRODUCTION

REVIEW

The evolution of the placenta


R MichaelRoberts1,2, Jonathan AGreen2 and Laura CSchulz3
1

C.S. Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA, 2Division of Animal Sciences,
University of Missouri, Columbia, Missouri, USA, and 3Department of Obstetrics, Gynecology and Womens Health,
University of Missouri School of Medicine, Columbia, Missouri, USA
Correspondence should be addressed to R M Roberts; Email: robertsrm@missouri.edu

Abstract
The very apt definition of a placenta is coined by Mossman, namely apposition or fusion of the fetal membranes to the uterine
mucosa for physiological exchange. As such, it is a specialized organ whose purpose is to provide continuing support to the
developing young. By this definition, placentas have evolved within every vertebrate class other than birds. They have evolved on
multiple occasions, often within quite narrow taxonomic groups. As the placenta and the maternal system associate more intimately,
such that the conceptus relies extensively on maternal support, the relationship leads to increased conflict that drives adaptive
changes on both sides. The story of vertebrate placentation, therefore, is one of convergent evolution at both the macromolecular and
molecular levels. In this short review, we first describe the emergence of placental-like structures in nonmammalian vertebrates and
then transition to mammals themselves. We close the review by discussing the mechanisms that might have favored diversity and
hence evolution of the morphology and physiology of the placentas of eutherian mammals.
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Introduction
Viviparity has evolved independently and seemingly
on multiple occasions across a diverse array of animal
groups, including invertebrates (Kalinka 2015). It is
a phenomenon whereby developing embryos are
retained within the reproductive tract, leading to release
of live offspring as an alternative to the more fecund
egg laying or spawning. One consequence of viviparity
is that the retained, fertilized egg must either survive off
its own reserves, usually yolk, or obtain some or part of
these resources from the mother. The latter situation, of
necessity, is expected to lead to increased conflict over
how provisions are partitioned between the supplier
and the recipient, thus potentially sparking a genetic
arms race. In turn, such conflict is expected to drive
adaptive changes that lead to a more intimate and
possibly more felicitous relationship between offspring
and the reproductive tract of the mother that favors the
transmission of both maternal and paternal genes to
the next generation, despite a loss of overall fecundity.
The transition from oviparity to viviparity and the
subsequent emergence of placentation within some
vertebrate taxa clearly required major changes in the
morphology and physiology of the reproductive tract
and has its origins well before the advent of mammals
(Van Dyke et al. 2014, Blackburn 2015). A placenta,
as defined originally by Mossman, is the apposition
or fusion of the fetal membranes to the uterine mucosa
for physiological exchange (Burton & Jauniaux 2015).
2016 Society for Reproduction and Fertility
ISSN 14701626 (paper) 17417899 (online)

It is a specialized organ whose purpose is to provide


continuing support to the developing young through the
provision of water, nutrients and gases, and to regulate
maternalfetal interactions often through hormone
production. By this definition, placentas have evolved
within every vertebrate class other than birds. Although
placentation arose once in the common ancestor of
mammals, it has arisen independently multiple times
within other classes, and even families. The story of
vertebrate placentation, therefore, is one of convergent
evolution at both the macromolecular and molecular
levels. In this short review of placental evolution, we
first describe the emergence of placental-like structures
in nonmammalian vertebrates and then transition
to mammals themselves. We close the review by
discussing mechanisms that might have favored diversity
and hence evolution of the morphology and physiology
of the placentas of eutherian mammals. Of necessity,
many important references cannot be cited in a short
review of this kind. Instead, we have attempted to direct
the reader to scholarly articles that do list the primary
source material.

Nonmammalian vertebrates
Cartilaginous fish
Viviparity is the most common mode of reproduction
in elasmobranchs. However, there is a wide range in
the degree of maternal provisioning of the embryo after
DOI: 10.1530/REP-16-0325
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ovulation (Wourms & Lombardi 1992), with embryos


of some species depending entirely on the yolk sac for
all of pregnancy, e.g. the spiny dogfish, which at birth
weighs 40% less than the yolk-filled fertilized egg from
which it develops. The tiger shark, by contrast, solves
such limiting provisioning; in which the dominant
embryo eats all of its littermates and any unfertilized
eggs before birth (Korsgaard & Weber 1989).
In the elasmobranchs, two placental types are
observed. Among stingrays, finger-like projections
of the uterine wall, termed trophonemata, provide
histotrophic nutrition to the developing embryo
(Hamlett etal. 1993), while the epithelium overlying
uterine blood vessels thins, lessening the barrier to
exchange. The mature embryo of the cownose ray, for
example, weighs 3000 times as much as the egg as a
result of reliance on the mother rather than the egg
yolk (Hamlett etal. 1993). A different placental type,
the yolk sac placenta, has evolved multiple times
in the ground sharks (Wourms & Lombardi 1992).
After the yolk has been consumed, the yolk sac
becomes modified into an umbilical cord region
and a placental region (Hamlett et al. 1993), which
become closely apposed to the epithelium of a highly
vascularized oviduct.
Teleosts
In Poeciliopsis fish, eggs are retained within the
follicle after fertilization and throughout embryonic
development (Wourms & Lombardi 1992). Most species
are lecithotrophic, relying on yolk, but in others, a highly
folded, follicular epithelium forms a follicular placenta
with the embryonic pericardial sac. This epithelial layer
is lined with microvilli, while the surrounding tissue is
highly vascularized, presumably to facilitate maternal
fetal exchange (Kwan etal. 2015). This type of placental
structure has arisen several times during Poeciliopsis
evolution (Kwan etal. 2015) and has been subsequently
lost and regained many times, making it a model for the
evolution of placentation (Pollux etal. 2014).
Among syngnathid fish (pipefish and seahorses) the
males, and not the females, become pregnant, after the
female transfers the fertilized eggs to a brood pouch
on the ventral side of either the trunk (Gastrophori) or
the tail (Urophori) of the males body. The degree of
contact and exchange between developing embryos
and the father range from minimal to situations that
display all the defining features of placentation (Wilson
etal. 2001). For example, in the straight-nosed pipe fish
Nerophis ophidion, eggs stick to the epithelium of the
fathers pouch, which is open to the sea environment
(Carcupino et al. 2002), while in the pot-bellied
seahorse Hippocampus abdominalis, the pouch is
sealed and its epithelium highly folded, thinned and
vascularized (Carcupino etal. 2002), thereby allowing
exchange of nutrients.
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Amphibians
Viviparity has arisen multiple times in amphibians,
accompanied in some cases with the evolution of
placentas. In frogs, there are examples in which the
tadpoles develop in the fathers mouth, in the mothers
stomach, or on the skin of the back (Wake 1993). In
the marsupial frogs, development occurs inside a
specialized maternal pouch on the back of the animal.
Following ovulation, secretory cells of the vascularized
pouch enlarge. The pouch epithelium is closely apposed
to specialized fetal gills, allowing exchange between
maternal and fetal circulations (Savage 2002). This, as
A.M. Carter wrote, would satisfy most peoples definition
of a placenta (Carter 2016). Arguably, however, a
structure found outside the reproductive tract, especially
following external fertilization that occurs in these frogs
and the sea horses described earlier, does not fit the
typical definition of a placenta. Nor have any of the gill
placentas of these endangered frog species yet been
shown to be the primary source of fetal nutrient support.
Reptiles
Viviparity occurs in more than 25 families of lizards
and snakes (squamate reptiles). Although estimated
by some to have arisen independently more than one
hundred times, it is conceivable that there was a single
origin of viviparity and multiple subsequent reversions
to oviparity (Pyron & Burbrink 2014, Van Dyke et al.
2014, Blackburn 2015). In many species, the embryo
relies on egg contents for nutrition, but in others a
range of adaptations of the female reproductive tract
provides a means to exchange gases and nutrients
with the conceptus (Stewart 2015). In squamates the
placenta is chorioallantoic, but unlike mammals it
does not develop from an early arising, extraembryonic
trophoblast layer. Most squamate placentas demonstrate
a simple interdigitation of the chorioallantois with the
uterine epithelium (Stewart 2015), but in some skinks
the interface is more intimate (Fig. 1). In the case of
the African skink Trachylepis ivensi, there is even a
degree of invasive implantation, with direct contact
between chorionic projections and maternal capillary
endothelium (Blackburn & Flemming 2012).
The chorioallantoic placenta of viviparous lizards can
be highly efficient in facilitating exchange of nutrients
and gases. Offspring of the Mabuya lizard weigh
500 times more at birth than the egg at fertilization,
indicating a nearly complete reliance for growth on
maternally supplied materials (Thompson & Speake
2002). There is also evidence for the expression of active
transporters at the sites of maternalfetal apposition in
some species (Murphy et al. 2011) and for placental
production of steroid hormones (Painter & Moore 2005).
Overall, where placentation occurs in squamates, it
bears a superficial resemblance to the epitheliochorial
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Figure1 Viviparity in reptiles: (A) Drawing from
a section of the mature chorioallantoic placenta
of the Australian skink Egernia cunninghami
carrying developing young, showing the
maternal capillaries closely adjoining the
allantoic capillaries on the fetal side. (B)
Drawing from a section of the immature
chorioallantoic placenta of the Australian skink
Egernia entrecasteaux. The section illustrates the
folded placental face likely involved in releasing
histotrophic material that can be taken up by the
chorionic ectoderm. Also, note the close
apposition of maternal blood capillaries with the
epithelium of the reproductive tract. The
diagrams are based on Fig. 15.5 and 15.7 from
E.C. Amorosos review on placentation
(Amoroso 1952), which were redrawn from
Weekes (1935).

placentation encountered in some eutherian mammals


and carries out many of the same functions, but its
formation does not involve the formation of a trophoblast
lineage, a feature unique to placental mammals.
Mammals
All mammals except the egg-laying platypus and the five
species of echidnas, the only surviving monotremes, rely
on a placenta for their reproduction. Indeed, the first
lineage decision made during embryonic development
of Mammalia is the segregation of cells that are destined
to become the external tissue layer of the placenta. This
lineage, usually called trophoblast (or, because it forms
the exterior of the conceptus, trophectoderm), diverges
early from the pluripotent lineage that advances to
form the inner cell mass. The cells that give rise to the
hypoblast and epiblast are unique to mammals. The
term trophoblast was first coined by Hubrecht (1904). Its
roots are tropho meaning nourishment, and blast for
embryonic. It is therefore questionable whether embryoderived placental cells of other animals, which unlike
mammals do not form an initiating trophectoderm,
should be termed trophoblast, despite many of their
shared functions. When and how trophoblast emerged
in the presumed metatherian ancestors of the Class
Mammalia is mysterious and unlikely ever to be revealed
from the fossil record.
Marsupials
Although eutherians are often referred to as placental
mammals, marsupials do possess placentas. However,
the placentas are short-lived and marsupials give birth
to relatively underdeveloped young. In marsupial
blastocyst, blastomeres adhere to the inner surface of the
zona pellucida, resulting first in a cup-shaped blastocyst,
and then a hollow sphere with no discernible inner cell
mass (Selwood & Johnson 2006). Both the embryonic
and extraembryonic lineages emerge from this single
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cell layer, with trophoblast materializing from the pole


of the blastocyst opposite the position of the future
embryo (Frankenberg etal. 2013, Morrison etal. 2013,
Familari etal. 2016). There are also indications that early
lineage specification may be controlled by a similar set
of transcription factors as in eutherians (Frankenberg
etal. 2013, Morrison etal. 2013, Familari etal. 2016).
The trophoblast cells originating from the marsupial
blastocyst combine with the yolk sac endoderm
and extraembryonic mesoderm to form a yolk sac
placenta, which can be bi- or trilaminar (Renfree 2010).
However, there are a species of koalas, wombats and
bandicoots, in which a chorioallantoic placenta forms,
but it appears to be supplementary to the main yolk sac
placenta (Freyer et al. 2003). Although the placentas
of marsupials are generally regarded as noninvasive
and of the epitheliochorial type (see next section), an
area of syncytium forms in the yolk sac placenta of the
gray short-tailed opossum and possibly related species.
This tissue makes direct contact with maternal blood
vessels (Zeller & Freyer 2001). Additionally, trophoblast
syncytialization (syncytial trophoblast; STB), where
adjacent cells fuse to produce cells with more than a
single nucleus, is accompanied by the expression of
an endogenous, retrovirus-derived protein, analogous
to what occurs in many eutherians (Cornelis et al.
2014). Another similarity to the eutherians is that the
placenta of the tammar wallaby secretes a complement
of hormones that include IGF2 and relaxin, which, in
that species, may be responsible for the phenomenon of
maternal recognition of pregnancy (Renfree 2010).
Eutherians
Origin of trophoblast: Eutherians consist over 5000
species in roughly 20 phylogenetic orders. Most of
our knowledge about their early development and the
events that lead to the initial specification of trophoblast
has been obtained only in a handful of these species,
especially the mouse. In mouse (Mus musculus), the
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first visible differentiation event, called compaction,


occurs between the 8 and 16 cell stage of embryonic
development, when the blastomeres polarize to form
extended contact zones with their neighbors and an
outward-facing apical surface (Posfai et al. 2014).
Further symmetrical and asymmetrical divisions follow,
so that by the 16 cell morula stage a population of
polarized cells exist on the cell surface, which becomes
trophectoderm, and another population of cells are
positioned inside, which is the precursor of the inner cell
mass (ICM). By the time of blastocyst formation, when
the mouse conceptus comprises about 32 cells, about
two-thirds of which are trophectoderm, the precursors
of extraembryonic endoderm (hypoblast) have begun to
segregate toward the base of the ICM. From this location,
they migrate outward to line the trophectoderm,
forming the yolk sac cavity. Later, extraembryonic
mesoderm joins with the trophectoderm to form what
at this stage is a bilayered chorion. Although there are
clear morphological similarities in the steps leading to
blastocyst formation in rodents, humans and domestic
mammalian species, there are differences in how
these events are timed and subsequently played out. In
many species, for example, mesoderm differentiates to
vascularize the yolk sac, forming a yolk sac placenta that
is eventually replaced by the chorioallantoic placenta.
Such a placenta does not form in humans, but persists
to term in rodents and lagomorphs. Similarly, compared
with the mouse, conceptuses from many species undergo
at least one further round of cell division before the
blastocoel cavity becomes visible. For details on how
placentas subsequently develop and begin to diverge in
morphology, the reader is directed to the still germane
reviews by Amoroso (1952) and Renfree (1982).
Range of placental morphologies: Despite the
spectacular diversity encountered in placental structure
at both the gross and microanatomical levels (Enders &
Carter 2004), there have been attempts over the years
to classify placentas and (somewhat unsuccessfully)
to relate the outcomes to mammalian phylogeny. For

example, placentas come in a range of shapes and sizes,


and have been placed in groups based on the general
gross morphologies of the sites where the chorion
attaches to the endometrium (Fig.2). They have also been
classified according to how many cell layers separate
the maternal and fetal circulations (Fig.2). A simplified
version of this system recognizes three main placental
types (Renfree 1982): epitheliochorial, in which there is
no erosion of the uterine epithelium; endotheliochorial,
where the invading trophoblast reaches but does not
penetrate maternal capillaries within the endometrium;
and hemochorial, where the trophoblast surface is in
direct contact with maternal blood (Fig. 3). A fourth
type, synepitheliochorial, has been recently used to
describe the placentas of ruminants (Wooding 1992).
Here, specialized trophoblast binucleated cells fuse
with uterine epithelial cells to form trinucleated cells,
a syncytium, or both. The placentas of ruminants, with
the exception of the phylogenetically more primitive
tragulids, are also characterized as cotyledonary
(Fig.2). Cotyledons are the primary sites of attachment
of the chorion to the endometrium and comprise tufts
of villous trophoblast that interdigitate and interlock
with complementary structures on the endometrium,
called caruncles. It is within these sites, often known
as placentomes, that binucleated cells, placental and
maternal blood capillaries, and placental interchange
are most concentrated. Therefore, this kind of placenta is
a derived form, secondary to the more superficial, diffuse
epitheliochorial type typical of most other artiodactyls.
Superficial vs invasive placentation: Intuitively,
it might be inferred that the least invasive types of
placenta, the kind where multiple cell layers separate
the two blood supplies (Fig. 2B), would be the most
inefficient and also the most primitive of all placental
types because there are more apparent physical barriers
to limit the movement of nutrients and dissolved gases.
Also, such placentas have a resemblance to placentas
described earlier for nonmammalian species, such as
skinks (Fig. 3). However, this is clearly not the case

Figure2 Cartoon illustrating the diversity of


placental morphologies encountered in
placental mammals.
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The evolution of the placenta R183

Figure3 Cartoon indicating how placentas can be classified according to the numbers and kinds of cell layers that separate the bloodstreams
of the mother and conceptus.

(Wildman et al. 2006). Compare, for example, the


relative maturity and independence of a newborn horse,
pig or whale, supported during their gestations by diffuse
epitheliochorial placentas, to a hapless pup born to a
mouse or a baby born to a human, species where the
placenta is hemochorial and discoid. Nor is the more
superficial form of placenta evolutionarily more ancient
than the kinds that are invasive and make direct contact
with maternal blood. On the contrary, careful analyses,
in which placental features were mapped to mammalian
phylogenies, have clearly dispelled this myth and
demonstrated that the epitheliochorial placenta is
not only a derived form that has evolved from a more
invasive placental type, but has arisen independently in
three distinct mammalian lineages, including primates
(Wildman et al. 2006) (Fig. 4). Moreover, this and
similar trees based on other features of the placenta
strongly imply that the placenta of the last common
eutherian ancestor was discoid, either hemochorial or
endotheliochorial (Mess & Carter 2007), and possessed
a labyrinth-type of placental interdigitation.
It should be stressed that the perceived disadvantages
of extended diffusion distances for dissolved gases and
solutes encountered with a superficial placenta, like that
of the pig, are largely illusory. As pregnancy proceeds,
the surfaces of the uterine and trophoblast epithelial
layers become interlocked (Fig. 5B). Capillaries on the
maternal and fetal sides come within a few microns of
each other (Fig.5A), often squeezing down to the tight
junctions between the trophoblast cells on the one
side and uterine epithelial cells on the other, probably
allowing efficient exchange of small molecules (Friess
et al. 1980). Movement of macromolecules that carry
essential components such as metals and vitamins is
more problematic, but an alternative strategy has been
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employed, namely the delivery of these components not


in the blood but in uterine secretions a process called
histotrophic nutrition (Fig. 5C) (Renegar et al. 1982).
The uterine glands of the pig, for example, release
uteroferrin, a bi-iron containing acid phosphatase to
supply iron. Uteroferrin and other proteins with a similar
provisioning function are taken up by specialized
regions of endocytic trophoblast cells congregated
in cup-like structures called areolae, which develop
opposite the mouths of each uterine gland (Fig. 5C).
From there, the maternal factors are transported via
the fetal bloodstream to the liver and other organs for
processes such as hematopoiesis (Renegar etal. 1982).
The likely advantages of a noninvasive placenta over the

Figure4 The evolution of the placental interface in terms of degree of


invasiveness of the placental tissue into maternal tissue, with
epitheliochorial being the least invasive and hemochorial being most
invasive. From Fig.2 of Wildman etal. (2006), with permission;
Copyright (2006) National Academy of Sciences, USA.
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Figure5 The porcine placenta: (A) Fetal


capillaries (FC) at day 58 of pregnancy
protrude deeply into the trophoblast, with the
diffusion distance between fetal bloodstream
and maternal uterine epithelium (UE) reduced
to a few micrometers; (B) At day 110 of
pregnancy maternal capillaries (MC) project
between uterine epithelial cells, bringing the
maternal and fetal capillaries within 35M;
(C) At day 30 of pregnancy, the microvilli on
the trophoblast surface (TR) interdigitate with
the ones on the uterine epithelium (UE) to
provide an intimate contact layer. Maternal
capillaries (MC) are placed just below the
basal lamina of the UE; (D) A general view of
a dome-shaped areola (AE) situated above the
mouth of a uterine gland (UG) at day 30 of
pregnancy. Figure 5AC are from Friess etal.
(1980); Fig.5D is from Friess etal. (1981)
with permission.

more primitive hemochorial and endotheliochorial types


include reduced exposure to the potential threats of the
maternal immune system, less damage to the uterus
associated with birth and elimination of the placenta,
and minimizing the transmission of fetal cells into the
maternal blood circulation and vice versa. Finally,
superficial placentation may limit disease transmission
between fetus and mother.
As the nature of the maternalfetal interface evolves,
so does the nature of the biochemical communication
possible between conceptus and mother. This is
particularly true in early pregnancy where there is an
urgency to interrupt estrous cyclicity and maintain
continued production of progesterone, if the pregnancy
is to continue (Bazer et al. 2009). As far as is known,
it is invariably the trophoblast that is responsible for
generating this signal for maternal recognition of
pregnancy, although the process is understood in only a
handful of species and even then rather poorly. What is
clear is that the mechanisms are highly variable, evolving
rapidly, and no one approach is used widely across taxa.
A couple of examples illustrate the kind of strategies
used in apes, where implantation occurs immediately
after the blastocyst attaches, and in artiodactyls, where
implantation is superficial and delayed. In the human and
most probably higher primates, but not in strepsirrhines
(lemurs and related species) that have a noninvasive
trophoblast, chorionic gonadotrophin (CG) provides
luteotropic support to the progesterone-producing cells
of the corpus luteum soon after implantation. In women,
hCG becomes measurable in blood and even in urine
by the second week of pregnancy, most likely as a result
of being released directly into maternal capillaries even
before the villous placental bed has formed (Roberts
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et al. 1996). In ruminant species, the pregnant mother


responds to the presence of the conceptus even before
the trophoblast has attached to the uterine wall. The
factor responsible is not a gonadotropin, but instead
a type 1 interferon- (IFNT), which acts on the uterine
epithelium, where it modulates the release of the
luteolytic factor, prostaglandin F2, that would normally
cause the corpus luteum to regress (Bazer et al. 1997,
Roberts etal. 1999). In pig, where maternal recognition
of pregnancy is also achieved during the period when
the conceptuses are elongating within the uterine lumen,
the anti-luteolytic factor appears not to be a protein,
but the steroid hormone estrogen (Spencer etal. 2007).
Selective mechanisms that may contribute to placental
diversity: It is generally recognized that there are
additional driving forces promoting adaptive changes
in the placenta and hence contributing to its rapid
evolution. One is undoubtedly the struggle for control
of maternal physiology in terms of nutrient allocation
(Fowden & Constancia 2012). As the demands of the
fetus increase, they will likely conflict with the ability
of the mother to provide such resources. An extensive
literature has developed around this topic, with
particular emphasis on the role played by imprinted
genes in controlling nutrient supply and growth of the
fetus (Reik etal. 2003). Many placental gene products,
including hormones and transporters, for example, likely
play a role in raising the concentrations of nutrients
in maternal blood and facilitating their uptake by the
placenta. There is, thus, a drive to keep the paternal
genes representing the fetus active, while silencing
the corresponding maternal alleles. Maternal efforts to
counteract the acquisitiveness of the fetus may lead to
the evolution of oppositely imprinted genes. Again, most
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speculation on the role of imprinted genes has come
from the mouse, with roles inferred for the human, both
species with an invasive placenta (Reik etal. 2003). Very
little is known about imprinting in those species where
there is little or no direct access of the trophoblast to
maternal blood, although data are beginning to emerge
(Chen etal. 2016).
A second force driving placental evolution is
undoubtedly the avoidance of immune rejection
(Hemberger 2013), a process still little understood,
although speculation abounds. It is assumed that to
minimize attention from various arms of the maternal
immune system, the trophoblast must continue to
evolve counter-measures for its own protection and even
advantage. These measures will undoubtedly be subtle
and complex and change as the degree of intimacy with
maternal system itself evolves. Some clues may emerge
by examining candidates encoded by rapidly evolving
genes and gene families within individual mammalian
clades, some of which are discussed in the next section.
Evolution of placenta-specific genes
Despite the observation that the initial lineage
regulators for trophoblast cell fate decisions may be at
least partially conserved across mammals, the resulting
placental structures and their associated trophoblast
cell populations appear not to be governed by
particular master genes. There are a few coding genes,
e.g., GCM1, a transcription factor that plays a role
in controlling the formation of syncytial trophoblast
(STB) (Cross etal. 2003) that appear to have an entirely
placental function in the sense that they have not
been implicated in developmental events outside the
trophoblast lineage. However, it seems likely that much
of the structural diversity and functional refinements
associated with mammalian placentas depend on
widely expressed transcription factors operating in a
combinatorial, but trophoblast-specific manner and
poorly understood processes linked to peculiarities in
the epigenetic landscape of trophoblast. There have
also been a large number of gene family expansions
(Rawn & Cross 2008). These gene families may be
performing roles in processes such as maternal
recognition of pregnancy, nutrient acquisition and
immune protection, thereby contributing to the unique
functional needs of different placental forms. It is worth
noting that placenta-specific in this context means that
such genes are disproportionately, but not necessarily
uniquely, expressed in the placenta. For example, it is
not unusual for some placenta-specific gene products
to be elevated in cancer and germ cells.
Placenta-specific gene families
Gene duplication provides a useful opportunity for
natural selection to operate (Hughes 1994) and allows
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the duplicated genes to acquire new functions, and,


through the acquisition or loss of regulatory regions,
changes in the temporal, spatial, or magnitude of
transcription compared with the original gene. Gene
family expansions associated with distinct placental
types have arisen repeatedly in eutherians (Rawn &
Cross 2008). Here, we provide four examples from the
many known placenta-specific gene families. In general,
assigning function of individual members within a family
will be difficult. Indeed, knockouts in mice performed
on single members of gene families have generally not
been informative, possibly because phenotype is not
obviously impaired within the friendly confines of a
vivarium, although it may become so when the pregnant
animal is under stress (Ain etal. 2004). Also, products
of multigene families likely overlap in function, so that
loss of one gene may be compensated by the presence
of one or more of its orthologs. Finally, family members
may even interact in an epistatic manner, providing a
combinatorial benefit not achieved by a single member
operating alone.
The growth hormone and prolactin-related proteins
are found in primates, rodents and ruminants and, most
likely, other taxa. Interestingly, gene family expansions
have occurred independently in these different lineages,
providing yet another example of convergent evolution.
Growth hormone (GH) and prolactin (PRL) themselves
arose from a common ancestral gene. In most species,
the GH gene is a single copy, but in humans, there
are five members, one restricted in expression to the
pituitary and the other four to the placenta (Haig 2008).
Their likely role is in resource allocation between the
fetus and the mother. By contrast, there is only a single
copy of the PRL gene in human, whereas there are 23
members in mouse, 24 in rat and 12 in cattle (Haig
1993). All except prolactin itself are expressed in
the placenta. In mouse, they have diverse patterns of
spatial and temporal expression (Simmons etal. 2008)
and appear to target the maternal endometrium (Soares
etal. 2007).
The pregnancy-specific glycoproteins (PSGs) are
secreted molecules that are abundantly produced by
primate and rodent placentas. They are related to the
carcinoembryonic antigen cell adhesion molecules
(CEACAM) found on the surface of certain tumors and
selected normal somatic cells. There are 10 intact PSG
genes in the human genome and 17 in mouse (McLellan
etal. 2005), although it is almost impossible to assign
orthologous members based on sequence identity.
Moreover, the organization of the domains in human
and mouse PSG proteins are quite different (McLellan
et al. 2005), raising the possibility that their roles in
primates and humans may not be identical. PSGs are
able to enter the maternal circulation and, in human,
can accumulate to extraordinarily high concentrations
in blood (200400
g/mL at term), but their roles
remain enigmatic.
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The interferon (IFN) proteins are products of the


filamentous conceptus of ruminants and have been
mentioned earlier in the context of maternal recognition
of pregnancy. They have been described in no other
taxa (Leaman & Roberts 1992). Within a species they
are well conserved, but considerable divergence
is evident in inter-species comparisons. They are
transcribed from multiple, structurally conserved
genes that have probably arisen by duplications and
gene conversion events from another type 1 IFN gene,
interferon omega (IFNW). Although builds of the
bovine genome have suggested IFN to be a relatively
small gene family (Walker & Roberts 2009), a large
number of gene variants have been described in each
species and even within single conceptuses, suggesting
that the families continue to diverge rapidly. The IFNT
proteins are secreted from mononucleated trophoblasts
and act on the uterus by binding to type I interferon
receptors, with the period of release occurring before
the trophoblast has formed definite attachment to the
uterine epithelium (Bazer et al. 1997, Roberts et al.
1999). Another notable feature of the IFN is that these
proteins have retained typical features of other type I
interferons, such as potent antiviral activity, although
their primary role has shifted to a reproductive
function. Conceivably, the progenitor gene product in
the common ancestor of present-day ruminants served
to protect the conceptus from viral infections.
The pregnancy-associated glycoproteins (PAGs)
are products of a gene family present in the placental
trophoblasts of swine and ruminants and most other
even-toed ungulates (Wallace et al. 2015). They are
related to aspartic proteinases, although some notably
lack the capacity to cleave protein substrates due to
modifications of normally conserved amino acids
around the active sites. The PAGs are particularly
complex in ruminants; in cattle, for example, there are
approximately two dozen members along with some
closely related paralogs. Most of the PAGs in ruminants
are expressed by specialized polyploid trophoblast
cells (binucleate giant cells) discussed earlier. After
fusion, the contents of secretory granules within the
binucleate cells are disgorged into the uterine stroma,
and many of the released PAGs enter the maternal
circulation and form the basis of useful pregnancy tests
for various ruminants, including dairy cows. The role
of PAGs is unknown, but their abundance suggests an
important function during pregnancy.
Endogenous retroviruses and retroviral elements
Ancestral retroviral infections have provided another
source of novel protein-coding genes that have played a
role in placental evolution. To ensure that the viral genes
do not replicate, the control elements of endogenous
retroviruses (ERVs) are usually highly methylated and
Reproduction (2016) 152 R179R189

effectively silenced. As a result, the fate of most ERVs


is gradual genetic degradation through mutation and
homologous recombination. Nevertheless, a minority
of ERVs retain a whole or partially intact open reading
frame potentially capable of producing a functional
protein (Weiss 2016). This point is particularly salient in
regard to the placenta, which in many species express a
range of ERVs that are involved in trophoblast function
(Denner 2016). Of those ERVs expressed in the placenta,
the most studied have originated from the envelope
(env) elements of the integrated viral DNA, and have
been called syncytins (Lokossou etal. 2014).
In humans, ERVW1 (syncytin-1) facilitates the fusion of
mononucleated cytotrophoblasts to form multinucleated
STBs (Mi etal. 2000). This process involves the interaction
of ERVW1 with a receptor, most probably the neutral
amino acid transporter, SLC5A1, on a neighboring cell.
The expression of ERVW1 is regulated by the placentaspecific transcription factor GCM1 discussed earlier, via
an enhancer element present in the long-terminal repeat
(LTR) of the gene (Lin et al. 2005). It is also notable
that ERVW1 is not involved in trophoblast fusion in
Old World monkeys, despite being present in their
genomes (Cceres et al. 2006). These animals make
use of a distinct syncytin, ERVV2, for STB formation.
Conversely, ERVV2 is expressed in human placenta but
does not appear to be involved in cytotrophoblast fusion
(Blaise etal. 2005). An important point illustrated here
is that expressed retroviral envelope genes (env) often
fulfill similar roles across species, but few represent
orthologous genes. Instead, the majority has arisen as a
result of independent integration events and coopted for
similar functions by different species.
A second env gene from a different endogenous
retrovirus (ERVFRD1; syncytin-2) is expressed in the
villous trophoblast of the human placenta (Blaise etal.
2003, Malassine etal. 2007) and is also believed to be
involved in trophoblast fusion events through interaction
with another transporter protein, MFSD2. ERVFRD1 has
been proposed to be immunosuppressive, an activity not
shared by ERVW1 (Mangeney etal. 2007). Several other
ERV proteins, e.g. ERV3-1, and ERVK family members,
including an antagonist of cell fusion (Sugimoto et al.
2013) are expressed in the placenta, but the roles of most
of them are even more obscure than that of ERVFRD1.
In mouse placenta, the labyrinth layer, which is
the functional equivalent of human floating villous
trophoblast, forms the transport surface in contact
with the maternal bloodstream. It is hemotrichorial,
i.e. it has a cytotrophoblast layer overlaid by two STB
layers (Dupressoir et al. 2009). Two syncytin genes
(Syna & Synb), products of separate integration events,
are expressed in this tissue. The SYNB protein is
primarily localized to the innermost STB layer, and, like
ERVFRD in the human, may have immunosuppressive
activity, as well as roles in facilitating cell fusion
www.reproduction-online.org


(Mangeney etal. 2007). Neither of these gene products,
however, is related to human syncytins, except for the
fact they are derived from ERV genes and are expressed
placentally.
Finally, endogenous retroviruses, with no obvious
homology to each other, have been described in the
placentas of a number of other species, including
marsupials, ruminants, carnivores and lagomorphs
(Denner 2016). In ruminants, they are mainly associated
with trophoblast binucleate cells that fuse with uterine
epithelial cells, but are assumed in all these species to
play roles that are somewhat similar to syncytins in the
human placenta.

Conclusions
Placentas, whatever their anatomic features, share a
number of common functions, all of which require
cooperative interactions with the maternal system.
Placentas deal with nutrient and oxygen import,
disposal of fetal waste products and gases, help to
physically retain the conceptus in the reproductive
tract, commandeer the local maternal blood supply
in some manner, release factors including metabolic
hormones to adjust the needs of the fetus to the
resources provided by the mother, and provide
immune protection. Yet, despite these apparently
conserved functions placentas are arguably the least
conserved and the most rapidly evolving mammalian
organs. These changes are speculated to be driven, at
least in part by maternalfetal conflict (Haig 1996).
Placental divergence has, in turn, been promoted
by selection for multiple kinds of genetic changes
including (1) duplications and gene conversion
events to create large gene families that themselves
are continuing to diverge extensively; (2) co-opting of
endogenous retrovirus-derived genes and gene control
elements; (3) rapid evolution of placenta-specific
enhancers and promoter elements; and (4) imprinting.
It is also possible that the hypomethylated state of
the placental genome (Chuong 2013) has permitted
relaxed silencing of gene control elements, including
those of ERVs. Perhaps this feature of the placenta sets
the stage for increased opportunity for epistasis the
interactions of genes that are not allelic. For example,
a harmful mutation in one gene may occasionally
become beneficial and confer increased fitness in
the presence of a mutation in another gene (sign
epistasis) (Weinreich et al. 2005), possibly allowing
both mutations to become fixed and the placenta to
adapt to the constraints of a changing environment.

Declaration of interest
The authors declare that there is no conflict of interest that
could be perceived as prejudicing the impartiality of the
research reported.
www.reproduction-online.org

The evolution of the placenta R187

Funding
Support was received from Missouri Mission Enhancement
Funds (L C S), Food for the twenty-first century program at the
University of Missouri (R M R & J A G), and a NIH Eunice
Kennedy Shriver National Institute of Child Health and Human
Development Grant (R01 HD069979) (R M R).

Acknowledgements
The authors thank Dennis Reith for editorial help, and Susan
Roberts, Nico Zevallos and Dr Ye Yuan for assistance in
preparing the figures.

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Received 15 June 2016


First decision 11 July 2016
Revised manuscript received 13 July 2016
Accepted 1 August 2016

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