animal
Animal (2014), 8:s1, pp 64–69 © The Animal Consortium 2014
doi:10.1017/S1751731114000470
Maternal-embryo interaction leading up to the initiation of
implantation of pregnancy in cattle
P. Lonergan† and N. Forde
School of Agriculture and Food Science, Belfield, Dublin 4, Ireland
(Received 5 December 2013; Accepted 7 February 2014; First published online 28 March 2014)
Early embryo development following fertilization occurs in the oviduct. However, despite being the site of fertilization in cattle, it is
possible to by-pass the oviduct by producing embryos in vitro and/or by transferring blastocysts recovered from one female into the
uterus of another. While there is substantial evidence for the oviduct having an influence on the quality of the developing embryo,
manifested in altered morphology, gene expression and cryotolerance, evidence for a two-way dialogue is weak. In contrast,
successful growth and development of the post-hatching blastocyst and pregnancy establishment are a result of the two-way
interaction between a competent embryo and a receptive uterine environment. Progesterone (P4) plays a key role in reproductive
events associated with establishment and maintenance of pregnancy through its action on the uterine endometrium. Elevated
concentrations of circulating P4 in the immediate post-conception period have been associated with an advancement of conceptus
elongation, an increase in interferon-tau production and, in some studies, higher pregnancy rates in cattle. This review summarizes
current knowledge on the communication between the developing embryo and the maternal reproductive tract.
Keywords: embryo mortality, endometrium, conceptus, pregnancy, bovine
Implications
Embryo mortality is a serious issue in cattle, particularly dairy
cattle, and can have a significant impact on profitability,
especially in a pasture-based system where there is a narrow
window of opportunity in which to get cows back incalf after
calving. Interaction between the developing embryo and the
maternal reproductive tract is essential for the establishment
of pregnancy and asynchrony between these two players can
result in compromised embryo development and or reduced
uterine receptivity.
Introduction
Following ovulation, fertilization of the oocyte occurs in the
oviduct and the resulting embryo moves towards the uterus
as it undergoes the first cleavage divisions. The bovine
embryo enters the uterus at about the 16-cell stage on
approximately Day 4 of pregnancy. It subsequently forms a
tight ball of cells referred to as a morula, in which the first
cell-to-cell tight junctions are formed. By Day 7 the embryo
has formed a blastocyst consisting of an inner cell mass,
which after further differentiation gives rise to the embryo/
†
E-mail: [email protected]
foetus, and the trophectoderm, which ultimately forms the
placenta. After hatching from the zona pellucida on Days 9 to
10, the spherical blastocyst begins to grow and change
in morphology from a spherical to ovoid shape during a
transitory phase preceding the elongation or outgrowth of
the trophectoderm to a filamentous form that usually begins
between Days 12 and 14. The ovoid conceptus is about 2 mm
in length on Day 13 and then reaches a length of about
60 mm by Day 16; however there is significant variation in
conceptus length at this time. Elongated conceptuses can be
readily recovered by standard uterine flushing techniques up
to Day 19, after which time the fully elongated conceptus
begins implantation with firm apposition and attachment of
the trophectoderm to endometrial luminal epithelium (LE)
(Guillomot et al., 1981). The objective of this manuscript is to
briefly review maternal-embryo/conceptus interaction around
the time of pregnancy establishment in cattle.
Interaction between the developing embryo
and the oviduct
Despite, clear evidence of an interaction between the
developing conceptus and the uterine endometrium in early
pregnancy (see below), the evidence for reciprocal cross-talk
during the transit of the embryo through the oviduct is less
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Maternal-embryonic interaction in early pregnancy
clear. Up to the blastocyst stage, the embryo can be considered somewhat autonomous (i.e. does not need contact
with the maternal reproductive tract). A few lines of evidence
support this statement; for example, using in vitro fertilization (IVF) technology, it is possible to produce large numbers
of bovine blastocysts in vitro by aspirating ovarian follicles,
maturing and inseminating oocytes in vitro and culturing the
resulting zygotes for about 7 days (Gordon, 2003). These
embryos have never been in an oviduct but are nonetheless
capable of establishing a pregnancy after transfer to the
uterus of a synchronized recipient. This would suggest that
the early embryo does not need exposure to the oviduct and
also that the oviduct does not need exposure to the embryo
in order for pregnancy to be established. In a similar vein, in
commercial bovine embryo transfer practice, early (~7-day
old) embryos are typically recovered from superovulated
donors and transferred to the uterus of non-pregnant synchronized recipients which, up to that stage, have not seen
an embryo. This again suggests that the reproductive tract
(of the recipient, in this case) does not need exposure to an
embryo before Day 7 to establish a pregnancy. Indeed, taken
to its extreme, it is possible to establish a pregnancy in a cow
by transferring embryos as old as 16 days (Betteridge et al.,
1980), that is, up to the time when the luteolytic mechanisms
would normally be initiated, although this would not be
practicable due to the filamentous nature of the conceptus at
this stage.
There is very convincing evidence for an effect of the oviduct on the quality of the early embryo. For example, shortterm culture of in vitro produced zygotes in the oviducts of
sheep (Enright et al., 2000; Rizos et al., 2002), cattle (Tesfaye
et al., 2007) or even mice (Rizos et al., 2007 and 2010) has
been shown to improve embryo quality, measured in terms of
morphology, gene expression, cryotolerance and pregnancy
rate after transfer. In contrast, relatively little evidence exists
of an effect going the other way (embryo to oviduct). The
limited data reporting an effect of gametes on the oviduct
come from litter-bearing species, where any effect is likely to
be amplified (Lee et al., 2002; Fazeli et al., 2004; Alminana
et al., 2012). We have recently characterized the transcriptome of the bovine oviduct epithelium on Day 3 post
oestrus in pregnant and cyclic heifers, corresponding to the
initiation of embryonic genomic activation (Maillo et al.,
2014). While large differences in gene expression were
observed between the isthmic and ampullar regions of the
oviduct, preliminary analyses suggest that the presence of an
eight-cell embryo had no effect on the transcriptome of the
isthmus (from where all unfertilized oocytes and eight-cell
embryos were recovered in cyclic and inseminated animals,
respectively), although a local effect at the precise position of
the embryo cannot be ruled out.
Temporal changes have been reported in the oviduct
epithelium gene expression during the oestrous cycle
(Bauersachs et al., 2004) between Day 1 and Day 12. However, the physiological relevance of these data is unclear
given that the embryo leaves the oviduct by about Day 4.
Many of the changes in gene expression described are likely
due to the difference in circulating progesterone (P4) (<3 v.
>12 ng) reported in the study. Furthermore, Hugentobler
et al. (2010) characterized the effects of changes in systemic
P4 (achieved by infusion of P4) on amino acid, ion and
energy substrate composition of oviduct and uterine fluids on
Days 3 and 6, respectively, of the oestrous cycle in cattle.
P4 increased uterine glucose, decreased oviduct sulphate
and, to a lesser degree, oviduct sodium, but had no effect on
any of the ions in the uterus. The most marked effect of P4
was on oviducal amino acid concentrations; nine of 20 amino
acids increased following supplementation, with glycine
showing the largest increase of approximately two-fold
whereas in the uterus only valine was increased.
Interaction between the developing embryo
and the uterus
As outlined above, despite the importance of the oviduct as
the site of fertilization in mammals, it can be readily by-passed
using IVF/ET technology. In contrast, the development of
the post-hatching and pre-implantation conceptus is entirely
maternally driven. The protracted period of implantation characteristic of ruminants and pigs involves rapid proliferation of
the trophectoderm cells, which is dependent on substances in
the uterine lumen, termed histotroph, that are derived from the
endometrium, particularly the uterine glands, for growth and
development. This is clearly demonstrated by the fact that:
(i) post-hatching elongation does not occur in vitro (Brandao
et al., 2004; Alexopoulos et al., 2005); and (ii) the absence of
uterine glands in vivo results in a failure of blastocysts to
elongate (Gray et al., 2002; Spencer and Gray, 2006). In recent
years, we and others have made significant progress in clarifying the role of diestrus P4 in the successful establishment of
pregnancy in cattle, with particular emphasis on how P4 affects
conceptus elongation. Using a combination of in vitro embryo
production and in vivo embryo transfer techniques, we have
shown that the effect of P4 on conceptus development is
mediated exclusively via the endometrium (Clemente et al.,
2009). Addition of P4 to culture medium had no effect on
blastocyst formation (Clemente et al., 2009; Larson et al.,
2011) or elongation after transfer to synchronized recipients
(Clemente et al., 2009). Most convincingly, the embryo does
not need to be present in the uterus during the period of P4
elevation in order to benefit from it (Clemente et al., 2009;
O’Hara et al., 2014), strongly suggesting that the effect of P4
is via advancing the endometrial transcriptome (Forde et al.,
2009) resulting in advancing conceptus elongation (Carter
et al., 2008; Clemente et al., 2009). In addition reducing the
output of P4 from the CL results in a delay in the temporal
changes in the endometrial transcriptome resulting in delayed
conceptus elongation in vivo (Forde et al., 2011a and 2012a).
On the maternal side, preparation of the uterine LE for
attachment of trophectoderm and implantation in all studied
mammals, including ruminants, involves carefully orchestrated
spatio-temporal alterations in gene and protein expression
and localization within the endometrium. In both cyclic and
pregnant animals, similar changes occur in endometrial gene
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Lonergan and Forde
expression up to initiation of conceptus elongation (approximately Day 13), suggesting that the default mechanism in the
uterus is to prepare for, and expect, pregnancy (Forde et al.,
2011b). Indeed, as mentioned above, it is possible to transfer an
embryo to a synchronous uterus 7 days after oestrus and
establish a pregnancy, as is routine in commercial bovine
embryo transfer, and even up to Day 16. It is only in association
with maternal recognition of pregnancy, which occurs on
approximately Day 16 in cattle, that significant changes in the
transcriptomic profile are detectable between cyclic and pregnant endometria (Forde et al., 2011b; Bauersachs et al., 2012),
when the endometrium responds to increasing amounts of
interferon-tau (IFNT) secreted by the filamentous conceptus.
Changes to the uterine environment during the
oestrous cycle in cattle
During the oestrous cycle an adequate rise in the post
ovulatory concentrations of P4 drives the ‘normal’ temporal
changes that occur in the endometrial transcriptome. These
are necessary to drive the changes required in the endometrium (and resulting histotroph), in order to provide the
embryo/conceptus with the nutritional requirements it needs,
which change as the embryo undergoes distinct morphological
events. Data on the pre-hatching embryo indicate that the
expression of a large number of genes and pathways (Forde
et al., 2009, 2011b and 2012a), including aminopeptidase,
lipoprotein lipase and lactotransferrin (Forde et al., 2010) amino
acids, ions and glucose (Hugentobler et al., 2007 and 2008) as
well as proteins in the histotroph including Ezrin, triosephosphate isomerase, Glutathione S transferase mu, Cathepsin D,
Annexin A1, which were more abundant in the histotroph than
in circulation (Faulkner et al., 2012). This expression pattern is
governed, in part, by the expression of the nuclear P4 receptor
(PGR) in the LE and glandular epithelium (GE). In general,
although this uterine environment is adequate for nourishing
the development embryo, it is not conducive to driving conceptus elongation, or indeed allowing uterine receptivity to
implantation.
Following adequate exposure to P4, the PGR is downregulated from the LE and GE allowing uterine receptivity to
implantation. Coordinate with this event is an alteration in
the overall transcriptional profile of the endometrium (Forde
et al., 2012a and 2013) allowing the switching on of genes
(and their protein products) that have been shown to drive
conceptus elongation in cattle or other species. This includes
the increased expression and or secretion of the proteins
IGFBP1 (Simmons et al., 2009), GRP, APOA1, ARSA, LCAT,
NCDN, PLIN (Forde et al., 2013), Legumin, TIMP2 (Ledgard
et al., 2009) and RBP4 (Costello et al., 2010; Mullen et al.,
2012) into the uterine lumen where they are available to help
promote conceptus elongation.
In spite of these normal changes in the uterine environment
caused by exposure to P4 in circulation, manipulation of
P4 modifies the endometrial transcriptome and uterine
environment with the subsequent effect on the developmental rates of the conceptus. First, supplementation with
exogenous P4 advances the down-regulation of the PGR
(Okumu et al., 2010) while delaying the output of P4 from
the CL, delays the down-regulation of the PGR (Forde et al.,
2011a). This has consequences for the expression of genes
that contribute to the histotroph; elevating P4 advances or
increases the expression of genes while low P4 delays or
decreases the expression of genes known to be important for
histotroph composition including ANPEP, APOA1, DGAT2,
FABP3, IGFBP1, IHH, LCAT, LPL, LTF, MEP1B, NID2, NMN,
NPNT, NXPH3, PENK, PLIN2, PRSS23, RBP4, SCG5, SERPINA14,
TINGAL1 and TFF3 (Costello et al., 2010; Forde et al., 2011a
and 2012a; Mullen et al., 2012). The P4 modification of the
expression of these genes, and in some cases their protein
products, results in a change in the capacity of the uterus to
support conceptus elongation.
Gene expression in the conceptus
Conceptus–maternal communication is vital for the successful
establishment and maintenance of pregnancy, yet relatively
little information exists for many of the mechanisms and the
nature of the conceptus signals responsible for this cross-talk.
Sub-optimal communication, resulting from impairment of
conceptus development and/or from abnormal uterine
receptivity, contributes to a high incidence of embryonic
mortality. Therefore, detailed examination of the mechanisms regulating both pre- and peri-implantation conceptus
development are necessary to fully understand the factors
regulating successful post-hatching development, pregnancy
recognition and implantation signalling. Despite significant
progress in our understanding of the temporal changes in the
transcriptome of the uterine endometrium, our knowledge of
the genes and pathways governing growth and development
of the bovine conceptus is still evolving. Furthermore, despite
a large number of studies describing gene expression profiles
in bovine embryos (up to and including Day 7, relatively little
information exists for the post-hatching embryo and elongating conceptus. This is, in part, a reflection of the fact that
such embryos are relatively easy to obtain in vivo (following
superovulation, artificial insemination and non-surgical uterine
flushing) and can be obtained in very large quantities following
in vitro embryo production using oocytes derived from the
ovaries of slaughtered animals. However, the post-hatching
period of development is arguably more important as a significant proportion of all embryonic loss occurs between Days 8
and 16 of pregnancy in cattle (Diskin and Morris, 2008), corresponding to the time of hatching of the blastocyst and its subsequent elongation coincident with the time of maternal
recognition of pregnancy in cattle.
A variety of studies in cattle, including studies from our
own group (Forde et al., 2009 and 2010), evaluated genes
expressed in the endometrium of the uterus during selected
stages of the oestrous cycle and pregnancy (Bauersachs
et al., 2005, 2006 and 2008; Mitko et al., 2008; MansouriAttia et al., 2009). However, data on gene expression during
the post-hatching embryonic stages in cattle are sparse and,
apart from a few exceptions, typically deal with candidate
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Maternal-embryonic interaction in early pregnancy
genes rather than being global in nature (Ushizawa et al.,
2004; Hue et al., 2007; Degrelle et al., 2011). Surprisingly,
the biochemical and molecular aspects of conceptus/endometrial interactions and blastocyst growth and conceptus
development during early pregnancy are not well defined.
Using a bovine utero-placental specific cDNA microarray,
Ushizawa et al. (2004) analyzed the changes in transcript
abundance in the bovine embryos on Days 7, 14 and 21,
extra-embryonic membranes on Day 28 and foetuses on
Days 28. The expression of 680 genes was up-regulated and
26 genes down-regulated from Day 7 to Day 14 including those
encoding for enzymes, transcriptional regulators, oncogenes,
tumour suppression, cell cycle control and apoptosis. A total
of 452 genes were significantly up-regulated from Day 14
through Day 21 with only two being down-regulated.
Degrelle et al. (2005) compared gene expression in ovoid,
tubular and filamentous conceptuses and presented data
supporting an important role of the ovoid stage during
blastocyst growth and differentiation. The persistent expression
of epiblast (Oct-4. Sox2, Nanog) and endoderm (Gata-6) specific
genes, the detection of markers of proliferation (Opn, Nap1L1)
and the expression of trophoblast-specific genes (Cdx2, Hand1,
Ets-2, IFNT) at the ovoid stage suggests it is an essential transition in polar and mural trophoblast development.
We have examined the temporal changes in transcriptional
profile of bovine embryo as it develops from a spherical blastocyst on Day 7 to an ovoid conceptus at the initiation of
elongation on Day 13 and to highlight differences in these
temporal gene expression dynamics between in vivo- and
in vitro-derived blastocysts which may be associated with
embryonic survival/mortality (Clemente et al., 2011). The main
findings of this study were that: (1) major temporal changes
occur in the embryo transcriptome between the blastocyst stage
on Day 7 and the initiation of conceptus elongation on Day 13;
(2) these changes are related to the environment to which the
embryo is exposed up to the blastocyst stage (i.e. in vivo v.
in vitro), with marked differences appearing in the transcriptome of the Day 13 embryo depending on its origin which
are reflective of its subsequent developmental fate and (3)
there is a panel of differentially expressed transcripts between
Day 7 and Day 13 which are common to both in vivo- and
in vitro-derived embryos and which are likely essential for
initiation of elongation. Similarly, groups of genes were
uniquely associated with in vivo derived embryos (i.e. potentially preferentially associated with increased embryo survival),
while others were uniquely associated with in vitro-derived
embryos (i.e. potentially preferentially associated with an
increased likelihood of embryo mortality).
Using RNA sequencing, Mamo et al. (2011) described the
temporal changes in transcriptional profiles of the bovine
conceptus at five key stages of pre- and peri-implantation
development from a spherical blastocyst on Day 7 through
Days 10, 13, 16 and 19, covering the critical period of the
formation of an ovoid conceptus, initiation of elongation,
maternal recognition of pregnancy to a filamentous conceptus at the initiation of implantation on Day 19. Compared
with previous studies, a large number of transcripts were
discovered in each of these key developmental stages,
including novel transcripts. The majority of these transcripts
were commonly detected across the five development
stages. However, significant differences were observed in the
abundance of each particular gene across the five different
developmental stages. Further analysis of these stage-specific
transcriptional changes may explain the accompanied morphological changes and reveal the relative importance of a
particular gene cluster during a particular developmental
stage. Generally, based on the abundance during each
developmental stage, the top 20 genes that appeared in
most stages include, various trophoblast kunitz domain
proteins, pregnancy-associated glycoproteins, cytoskeletal
transcripts, heat shock proteins, calcium-binding proteins,
APOA1, AHSG, BOP1, TMSB10, CALR, APOE, TPT1, BSG,
FETUB, MYL6, GNB2L1, PRDX1, PRF1, IFNT and FTH1. Analysis of variance followed by self organizing map analysis
revealed nine gene clusters with distinct stage-specific
expression profiles containing a large number of known
and novel transcripts that may play key physiological roles
during the various stages of conceptus development (Mamo
et al., 2011). Most of the detected genes have not been
previously characterized in the bovine conceptuses; therefore, establishing their functions, as well as horizontal and
vertical relationship during various stages of conceptus
growth and development will provide insight into their
respective roles. The reader is referred to (Mamo et al., 2011)
for the details.
Conceptus-induced effects on the endometrium
It has been well established that the endometrium is modified
by stage of the cycle and concentrations of P4 in circulation
but the mechanisms to drive conceptus elongation and
endometrial receptivity to implantation are established irrespective of whether an embryo is present, at least up to
pregnancy recognition (see above). It is only when IFNT
secretion from the conceptus is sufficient to induce the
pregnancy recognition response in both the endometrium
and in the extra uterine environment, that divergences
between the pregnant and non-pregnant uterus are established. In general, these differences are detectable by Day 15
or Day 16 of pregnancy (Forde et al., 2011b; Bauersachs
et al., 2012) and the major changes identified include
response to a Type I Interferon, of which IFNT is one. This
includes the up-regulation of ‘classical’ interferon-stimulated
genes (ISGs) such as ISG15, (Johnson et al., 1998), MX1 and
MX2 (Hicks et al., 2003), OAS1, BST2, B2M, CXCL10, STAT1,
STAT2, PTX3, EIF4E, USP18 (Forde et al., 2011b) Indeed in
the last number of years there have been quite a number of
large transcriptomic studies performed on gene expression
changes in the endometrium of pregnancy compared with
non-pregnant or cyclic heifers. Despite the different platforms
used for analysis, breed of animal and different data analysis
methods Bauersachs et al. (2012) used gene set enrichment
analysis to reveal a conceptus-induced signature in the endometrium across numerous studies on Days 15, 16, 17, 18 and 20.
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Lonergan and Forde
What is clear from all these data is that the conceptus elicits a
distinct gene signature in the endometrium during the process
of pregnancy recognition. Indeed, evidence that the endometrium can act a sensor of the quality of the embryo was recently
provided by two elegant studies examining the endometrial
transcriptomic response elicited by conceptuses of differeing
developmental fates (Bauersachs et al., 2009; Mansouri-Attia
et al., 2009; reviewed by Sandra et al. (2011)). Some, but not all,
of the differentially expressed genes were involved in the classical IFNT response of the endometrium MX2, BST2, IFIT1
(Bauersachs et al., 2009); radical S-adenosyl RSAD2, OAS1
(Mansouri-Attia et al., 2009).
There is some evidence from other models (notably the
sheep) that the conceptus produces other molecules aside
from IFNT that act on the endometrium including prostaglandins (PG) (Dorniak et al., 2012) and cortisol (Dorniak
et al., 2013). More recently, using a model of multiple
embryo transfer that is where the effect of the conceptus
during the ovoid stage is amplified, we have demonstrated
there is increased PG in the uterine lumen compared with
control heifers. Moreover, increased PG seems to induce the
expression of some ISGs in the endometrium before IFNT
acting on the endometrium to further stimulate their
expression (Spencer et al., 2013). Further evidence that the
conceptus itself produces factors that affect the endometrium is that differences (although quite subtle) between
pregnant and cyclic heifers were identified on Day 13 of
pregnancy in the endometrium of heifers using RNA
sequencing, but these genes were not regulated by short-term
exposure to IFNT (Forde et al., 2012b). Also, comparison of
endometrium tissue recovered from pregnant heifers to those
exposed to IFN α in the uterine lumen for 2 days, revealed
that not all genes induced by the conceptus are regulated
by IFN (Bauersachs et al., 2012). Collectively these data
demonstrate that, although the main molecule affecting the
endometrium is IFNT, additional molecules, some of which
have yet to be identified, may also play a role in conceptus
maternal interactions.
Conclusion
In conclusion, there is significant evidence that exposure
of the embryo to the oviduct benefits the embryo but with
little evidence that the embryo itself elicits an effect on
the oviduct. There is considerable evidence that changes to
the endometrium (and subsequent histotroph) modulate the
environment to which the embryo is exposed and affect the
ability of the uterus to drive conceptus elongation. In addition
to maternal to embryo communication, there is reciprocal
cross-talk from the conceptus to the endometrium; this is
mainly mediated by IFNT but there is new evidence that
the conceptus modulates the endometrium by secreting
molecules other than IFNT, including PGs.
Acknowledgements
The authors’ work cited here has been supported by grants from
Science Foundation Ireland.
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