Hosting the preimplantation embryo: potentials ... - CSIRO Publishing

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Reproduction, Fertility and Development, 2013, 25, 62–70 http://dx.doi.org/10.1071/RD12279

Hosting the preimplantation embryo: potentials and limitations of different approaches for analysing embryo]endometrium interactions in cattle Susanne E. Ulbrich A,C, Eckhard Wolf B and Stefan Bauersachs B A

Physiology Weihenstephan, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising, Germany. B Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universitaet Muenchen, Feodor-Lynen-Str. 25, 81377 Munich, Germany. C Corresponding author. Email: [email protected]

Abstract. Ongoing detailed investigations into embryo–maternal communication before implantation reveal that during early embryonic development a plethora of events are taking place. During the sexual cycle, remodelling and differentiation processes in the endometrium are controlled by ovarian hormones, mainly progesterone, to provide a suitable environment for establishment of pregnancy. In addition, embryonic signalling molecules initiate further sequences of events; of these molecules, prostaglandins are discussed herein as specifically important. Inadequate receptivity may impede preimplantation development and implantation, leading to embryonic losses. Because there are multiple factors affecting fertility, receptivity is difficult to comprehend. This review addresses different models and methods that are currently used and discusses their respective potentials and limitations in distinguishing key messages out of molecular twitter. Transcriptome, proteome and metabolome analyses generate comprehensive information and provide starting points for hypotheses, which need to be substantiated using further confirmatory methods. Appropriate in vivo and in vitro models are needed to disentangle the effects of participating factors in the embryo–maternal dialogue and to help distinguish associations from causalities. One interesting model is the study of somatic cell nuclear transfer embryos in normal recipient heifers. A multidisciplinary approach is needed to properly assess the importance of the uterine milieu for embryonic development and to use the large number of new findings to solve long-standing issues regarding fertility. Additional keywords: somatic cell nuclear transfer, transcriptomics, prostaglandins, uterus.

Introduction One of the most important issues negatively affecting reproductive success is early embryonic mortality (Humblot 2001; Thatcher et al. 2001). Embryonic losses occur mainly during the critical period of maternal recognition of pregnancy when conceptus-derived signals must communicate to the maternal endometrium to maintain pregnancy. During the oestrous cycle, the female reproductive tract undergoes a locally and timely synchronised reorganisation in order to meet the needs of the developing conceptus. The synthesis and secretion of oviductal fluid and uterine histotroph provide both crucial nutritious fluid (Hugentobler et al. 2008) and also serve as a mechanism for communication between the maternal environment and the conceptus (i.e. transport of signalling molecules and growth factors to the conceptus; Fazeli and Pewsey 2008). Signals are produced from the conceptus to Journal compilation Ó IETS 2013

suspend cyclicity and to prevent luteolysis until a stable environment has formed following implantation. In evolutionary terms, the concept of cyclicity is relatively young (Meyer 1994). In every cycle, the endometrium undergoes many processes of differentiation because within each cycle a potential pregnancy may be expected. Cyclicity provides an additional reproductive opportunity that has shown to be advantageous in large mammals. It is likely that, initially, the embryonic signals act locally, driving the maternal epithelium to create a beneficial microenvironment surrounding the embryo (Østrup et al. 2011). Subsequent amplification mechanisms by the maternal side facilitate the transmission of the initial signal to the periphery, causing endocrine changes in the mother. This implies a precise orchestration of reciprocal interactions essential for pregnancy outcome (Bazer et al. 2011). www.publish.csiro.au/journals/rfd

Hosting the preimplantation embryo

Models for analysing embryo]maternal interactions Descriptive changes of the endometrium and the embryo generated by high-throughput technologies allow hypotheses to be tested regarding both the driving factors of development and the possible effects of these factors (Bauersachs and Wolf 2012). However, it is a major challenge to handle the growing number of infinite lists of differentially expressed genes at transcriptional or translational levels. Descriptive analyses do not allow pinpointing of the drivers, players and free riders of biological events, even if in-depth studies are undertaken. In general, it is difficult to evidence communication, because parallel or opposing changes of two factors do not necessarily need to have a causal relationship. These changes may only reflect correlated but independent effects of higher-order regulators. Thus, a combination of further suitable models is needed to overcome the limitations of initial description (Spencer et al. 2008). Cattle provide an ideal animal model to decipher embryo– maternal cross-talk (Van Soom et al. 2010): They represent a target species of interest, cycle synchronisation is easily possible, AI and IVF are routinely established and sample collection ex vivo and in vitro is easy to perform. In addition, there are several analogies to humans with respect to protein sequence homologies, sex steroids and similarities in embryo development and gene structure (Elsik et al. 2009). Furthermore, in cattle, research with embryos is possible (embryo production, embryo splitting, somatic cell nuclear transfer (SCNT)), whereas it is obviously limited in humans. Finally, the possibility of in silico analyses using access to large genomic databases across several species and experimental set-ups holds numerous analytical possibilities for meta-analyses that may reveal valuable information currently idled. In vivo models are the ‘gold standard’ In vivo models are the gold standard that represents most adequately the complexity of physiological interactions. Heifers are commonly chosen model animals because they are a most homogeneous group and have a relatively high conception rate. In addition, heifers are not influenced by clinical implications with respect to earlier pregnancies or metabolic imbalances during early lactation. Numerous different in vivo models exist that address endometrial function. These comprise the analysis of different time points during the cycle and early pregnancy, substitution of hormones in ovariectomised animals and application of substances orally, systemically, intravaginally or into the uterus (Kimmin and MacLaren 2001; Emond et al. 2004; Forde et al. 2009; Ulbrich et al. 2010; Van Soom et al. 2010; Dorniak et al. 2011; Waters et al. 2012). One particularly interesting model has been the use of identical twins generated by embryo splitting as recipient cows for embryo transfer to exclude a maternal genetic effect (Klein et al. 2006). It would be interesting to expand the twin model to different external conditions to analyse a possible environmental effect on preimplantation development. If identical twin embryos were transferred to recipients of high and low fertility, different maternal effects on the development of the embryo might be found due to differences in endometrial receptivity.

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The essential contribution of a selected number of signalling molecules has been analysed in detail. The effect of exogenous interferon (IFN)-t has been studied by infusion into the uterus (Chen et al. 2006), by an intrauterine device slowly releasing IFN-a2 (Bauersachs et al. 2012) or by using a catheter ending at the uterotubal junction in the lumen of the uterine horn provided with a small osmotic pump to inhibit or substitute prostaglandins (Dorniak et al. 2011). However, it is difficult to reduce communication to a single signal, particularly when it is not clear which side is the target (e.g. in case of prostaglandins). In vitro cell culture systems complement in vivo models In the context of communication between the embryo and mother, the rationale of developing in vitro models is based on the difficulty of performing in vivo studies on such small entities within such a large space. In particular, it is difficult to identify the site where the embryo possibly exerts important local paracrine interactions with the maternal epithelium. Thus, experimental in vivo settings are complemented by suitable in vitro models (Rottmayer et al. 2006; Tithof et al. 2007; Meier et al. 2009; Ulbrich et al. 2010). These may help elucidate the intracellular mechanisms of signal transduction (Godkin et al. 2008). Somatic cell nuclear transfer pregnancies as a model for aberrant communication Analysing settings in which failure of normal development is frequently observed is helpful for unravelling communication signals. Observations from pregnancies with transferred embryos derived by different protocols of in vitro production (IVP) or SCNT indicate that these may be considered as appropriate models. Initial pregnancy rates after transfer of SCNT embryos are similar to AI or transfer of flushed embryos (Heyman et al. 2002; Lee et al. 2004), but continued pregnancy losses occur throughout the entire gestation period. Because reprogramming involves changes in the patterns of epigenetic markers, such as DNA methylation and histone modifications, failures of SCNT are most probably due to problems with reprogramming of a nucleus derived from a differentiated cell. The high rates of pregnancy failure in recipients of SCNT embryos have been linked to structural and functional abnormalities of the placenta (Chavatte-Palmer et al. 2012). Specifically, abnormally enlarged and fewer placental cotyledons (Hill et al. 2000; Batchelder et al. 2005) may originate from abnormal early implantation events or from disturbed embryo–maternal communication already before implantation. In these cases, the endometrium may suitably serve as a mirror reflecting abnormal embryonic signalling (Bauersachs et al. 2009; Mansouri-Attia et al. 2009a, 2009b; Groebner et al. 2011c). Maternal preparation for pregnancy Progesterone (P4) is considered the major steroid hormone required for the establishment and maintenance of pregnancy. During the luteal phase, P4 initially suppresses expression of oestrogen receptor a (ESR1) and oxytocin (OXT) receptor (OXTR) genes. However, after a period of P4 exposure, the cytosolic progesterone receptor (PGR) disappears from the

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luminal epithelium (LE) and resides in stromal cells. With the loss of epithelial PGR expression, the P4 block suppressing ESR1 and OXTR expression is lost, and the expression of ESR1 and subsequently OXTR increases, despite high circulating levels of P4. Rising oestrogen concentrations induce further upregulation of ESR1 and OXTR. After the decrease in PGR expression in the LE allowing an increase in ESR1 expression and/or after decreased endometrial P4 sensitivity, follicular oestrogens in the presence of oestrogen receptor (ER)-a stimulate OXTR expression, thus enabling OXT-induced pulsatile prostaglandin (PG) F2a secretion initiating luteolysis. The pulsatile PGF2a release from the bovine endometrium eventually triggering luteolysis and commencing oestrus is well described (Kindahl et al. 1976; Schams 1987; Wathes and Lamming 1995; McCracken et al. 1999). Endocrine hormones are essential for endometrial secretion Ruminants exhibit late implantation with a synepitheliochorial type of placentation. Uterine secretions from endometrial glands are essential for conceptus elongation and normal embryonic development before implantation, as evidenced from uterine gland-knockout (UGKO) ewes (Gray et al. 2001), in which embryo development arrests at the blastocyst stage, indicating that embryo elongation is inhibited. Thus, the histotroph synthesised and secreted by the endometrial glands, is a crucial source of nutrients. The induction of an early rise of progesterone after normal oestrus, using a progesterone-releasing intravaginal device (PRID), leads to enhanced embryo elongation (Carter et al. 2010). Vice versa, the reduction in circulating progesterone leads to altered endometrial gene expression and reduced capacity to enhance embryo elongation (Forde et al. 2011a), confirming the priming effect of progesterone on the histotroph. Because PGR expression is lost during the luteal phase in endometrial epithelial cells (Robinson et al. 1999, 2001), P4 cannot act by classical ligand-activated PGR binding to P4-response elements in the promoter region of target genes. Rather, the mechanism of activation must be either through residing low levels of progesterone receptor (PR) in epithelial cells or via stromal cells maintaining PR expression (Bazer and Slayden 2008). The latter is most likely because these stromal cells express growth factors that may act as ‘progestamedins’ and exert their paracrine function through membrane receptors on both epithelial cells (for endometrial histotroph synthesis) and trophoblast cells (promoting conceptus growth; Michael et al. 2006). This may have several implications. First, to understand P4-induced endometrial secretion, molecular analyses should focus on signalling molecules of progestamedin transduction pathways. Their respective binding elements in the promoters of genes encoding secretory proteins are specifically interesting, rather than PGR response elements (Bazer and Slayden 2008). Second, the non-genomic, rapid signalling PGR should be investigated further as a possible contributor to endometrial function (Stormshak and Bishop 2008). Maternal responses to pregnancy In ruminants, pregnancy recognition signals are antiluteolytic and prevent endometrial PGF2a secretion, causing luteal

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regression. The most important signal known to date is IFN-t, a Type I IFN that is secreted by the bovine trophoblast, with a marked rise during trophoblast elongation between Days 14 and 18 of up to 105 units h 1 in culture on Day 18 (Cross and Roberts 1991; Robinson et al. 2006). All Type I IFNs have antiviral, growth inhibitory and pro-apoptotic activities in common (Chawla-Sarkar et al. 2003; Wang et al. 2003). According to Roberts et al. (2003), a series of insertion events occurred in an ancestral IFN-v resulting in an IFNT gene that lost its facilitative operation of viral-induced expression and manifested as a trophectoderm-specific signalling molecule (Ealy and Yang 2009). Upon binding of IFN-t to the common Type I IFN receptor subunits IFNAR1 and IFNAR2 (Li and Roberts 1994), the Janus tyrosine kinase/signal transducer and activator of transcription signalling pathway is activated and the transcription of a variety of IFN-stimulated genes (ISG) is initiated. In the ewe, most ISG are not induced in the endometrial luminal epithelium and superficial glandular epithelium owing to inhibition of IFN regulatory factor (IRF) 2, but rather in the stroma and glandular epithelium (Choi et al. 2001). Because the IFNAR2 subunit is not expressed on trophoblast cells (Groebner et al. 2010), the embryo has a reduced susceptibility to its own IFN signalling (Han et al. 1997). Suspension of luteolysis and further endometrial remodelling by IFN-t It has been shown that IFN-t binds to IFNAR on luminal and glandular epithelial cells of the endometrium and suppresses the upregulation of OXTR (Spencer and Bazer 1995; Han et al. 1997; Robinson et al. 1999, 2001; Rosenfeld et al. 2002). At present, it is still a matter of debate whether IFN-t acts directly on the OXTR gene or via suppression of the ESR1 gene. Studies in sheep have indicated that ER-a appeared before OXTR (Spencer et al. 1996), and Fleming et al. (2006) reported that IFN-t had no effect on ovine OXTR promoter activity. Thus, IFN-t is thought to indirectly inhibit OXT-mediated stimulation of PGF2a (Spencer et al. 1996) via suppression of ESR1 transcription (Fleming et al. 2006), which thus impedes oestrogen-induced OXTR upregulation (Bazer et al. 2009). In the bovine, the antiluteolytic mechanism may be slightly different. Finding ER-a in the bovine endometrial luminal epithelium on Days 12–14 of the cycle (Robinson et al. 2001) may reflect a bovine-specific peculiarity that could require the direct binding of IRFs on OXR IFN-responsive elements (IRE) for preventing oestrogen-induced OXR upregulation in case of pregnancy (Mann et al. 1999; Telgmann et al. 2003). The bovine OXTR promoter region contains an IRE, and IRF1 and IRF2 bind to this site (Telgmann et al. 2003). Thus, inhibition of ESR1 would not necessarily be required in the cow (Robinson et al. 2008). Clearly, in the presence of IFN-t, PGF2a pulses impairing luteal function are absent (Bazer et al. 1997); however, the precise molecular mechanisms underlying the induction and inhibition of luteolysis remain to be unravelled. Important further biological activities are induced by embryonic signals during early pregnancy. Endometrial responses to the presence of an elongating embryo have been recently targeted in numerous singular and global transcriptome analyses (Bauersachs


et al. 2005, 2006, 2008; Klein et al. 2006; Mitko et al. 2008; Carter et al. 2010; Walker et al. 2010; Clemente et al. 2011; Mamo et al. 2011; Forde et al. 2011b, 2012; Forde and Lonergan 2012), as well as proteome analyses (Berendt et al. 2005; Arnold and Frohlich 2011; Mullen et al. 2012). The endometrium undergoes regulation of cellular turnover and adhesion and extracellular matrix remodelling to prepare the endometrium for the attachment and implantation of the conceptus, an endometrial vascular supply and histotroph synthesis. This allows the development of the fastgrowing trophoblast and modulation of the maternal immune system, including mechanisms of immunological adaptation. The effects of recombinant IFN-t and IFN-a on the endometrium in vivo and in vitro indicate that a large number of genes are IFN responsive (Emond et al. 2004; Gray et al. 2006; Bauersachs et al. 2012). However, it remains uncertain which genes actually have an action and which are evolutionary relics of the antiviral IFN response. Our studies have shown that IFN does not lead to enhanced apoptosis (Groebner et al. 2010) and does not augment enhanced regulation of immune cells as found in other species (Groebner et al. 2011b), nor does it induce complement activation (A. E. Groebner, S. Bauersachs, E. Wolf, H. H. D. Meyer and S. E. Ulbrich, unpubl. obs.). This may have been strongly suggested given the number of differentially expressed genes, specifically in context with the gene ontology term ‘immune response’ (Bauersachs et al. 2006; Klein et al. 2006; Walker et al. 2010). Either signalling pathways are not transduced and/or modulatory mechanisms exist to prevent negative effects of an antiviral response in the bovine endometrium caused by IFN-t (Hansen 2011). Thus, of the various molecules secreted, the challenge remains to identify those molecules that induce responses and those that do not. Thus, for further in vivo studies, the differential analysis of specific populations of endometrial cell types from carefully selected naturally synchronised animals is mandatory. Furthermore, suitable endometrial cell culture models must include stromal cells in coculture, even if the vascular system is lacking. This allows a more appropriate study of both the signal recognition pathways and the actions of progestamedins and IFN-t on steroid hormone stimuli and embryonic signalling, because a tight paracrine cross-talk between epithelial and stromal cells is likely to be of significance. Embryonic signalling beyond IFN-t Insufficient amounts of IFN-t or impeded recognition of IFN-t signalling from the maternal side have been shown to cause substantial loss of potential offspring, evidencing the pivotal role of IFN-t in suspending cyclicity (Humblot 2001; Thatcher et al. 2001). However, beyond IFN-t, further signals may be of crucial importance. This issue has been highlighted in recent studies comparing the endometrial transcriptome of early pregnancy with the endometrial profile induced by IFN-t and IFN-a (Bauersachs et al. 2012; Forde et al. 2012), in which several genes were found to be potential candidates. Pivotal role of PG as embryonic signals? The PG are important signalling molecules synthesised by both the endometrium and embryo (Arosh et al. 2003; Banu et al.


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2003; Kim et al. 2003; Madore et al. 2003; Emond et al. 2004; Parent et al. 2006). In vitro studies have shown that IFN-t can alter PG production by endometrial cells, namely a shift from PGF2a to PGE2 production (Asselin et al. 1997a), specifically at high doses (Guzeloglu et al. 2004). In this context, PGE2 is considered a luteoprotectant and luteotropin necessary for the support of luteal function. Intrauterine infusion of IFN-t has been shown to modulate PG production by endometrial cells, especially by increasing cyclo-oxygenase-2 and decreasing PGF synthase (Arosh et al. 2004). Thus, an optimal PGE2 to PGF2a ratio during pregnancy favouring PGE2 is generally accepted as an essential prerequisite maternal contribution for the successful establishment of pregnancy (Arosh et al. 2004). However, liquid chromatography tandem mass spectrometry evidenced the presence of PGI2 as the principal PG dominating the pregnant bovine uterus lumen, followed by PGF2a and PGE2 and finally PGD2 and thromboxane B2 (Ulbrich et al. 2009). The concentration in vivo was much higher during pregnancy, paralleling earlier findings in sheep (Ellinwood et al. 1979; Bartol et al. 1981; Marcus 1981; Lewis et al. 1982; Shelton et al. 1990). Concentrations of PGs were greatest on Day 15, when IFN-t concentrations were only starting to increase (Ulbrich et al. 2009), suggesting that the PG may appear concomitantly with or even earlier than IFN-t. Because the release of all PG examined was strikingly concomitant, a general rather than specific synthase may account for the increased levels of PGs. It is interesting to note that the lack of concurrent endometrial differential mRNA abundances would by no means have predicted such vast concentration differences of these signalling hormones. In contrast to many in vitro culture findings (Asselin et al. 1997a, 1997b; Parent et al. 2002; Emond et al. 2004; Tithof et al. 2007; Godkin et al. 2008), the PGE2 : PGF2a ratio did not change in vivo at the embryo–maternal interface (Ulbrich et al. 2009). Two possible explanations may account for these contentious findings: First, the known PG contribution of the embryo is neglected if studying the effects of IFN-t on PG production by endometrial cells, which may play an important role in vivo. Second, the cell populations of stromal versus epithelial endometrial cells may not resemble the actual in vivo situation because the vasculature is missing. Notably, by inhibiting cyclooxygenase, it has been shown in sheep that PG are essential for trophoblast elongation in vivo (Dorniak et al. 2011), that PG act in concert with IFN-t to influence endometrial function (Dorniak et al. 2012b) and that PG specifically induce important nutritional key components (Dorniak et al. 2012a). With this convincing evidence, it is of great interest to further disentangle the origin and mode of action of PG in the context of early pregnancy. Strikingly, transcriptome profiling of endometrial samples from recipients carrying SCNT embryos showed that several different genes were less abundantly expressed compared with those in IVF pregnancies (Bauersachs et al. 2009). Because abnormal patterns of reprogramming and altered trophoblast development have been reported (Dean et al. 2001; Santos et al. 2003), these differences may have arisen directly from altered signalling of the SCNT embryo itself. Interestingly, uterine flushings from SCNT pregnancies had significantly lower levels

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of PGI2 and PGE2 than pregnancies obtained with IVP embryos, although neither embryonic length nor uterine concentrations of IFN-t differed with respect to the origin of the embryos (S. E. Ulbrich, V. Zakhartchenko, H. D. Reichenbach, C. Angioni, G. Geisslinger, E. Wolf and H. H. D. Meyer, unpubl. obs.). The SCNT pregnancies showed an increase in the 15-keto metabolites of PGF2a and PGE2, indicating a reduced capacity of SCNT embryos to produce sufficient amounts of PG (S. E. Ulbrich, V. Zakhartchenko, H. D. Reichenbach, C. Angioni, G. Geisslinger, E. Wolf and H. H. D. Meyer, unpubl. obs.). Thus, bovine SCNT embryos may contribute to the altered PG environment in the uterine lumen either directly by synthesising insufficient amounts of PG or indirectly by inducing aberrant endometrial PG production and metabolism. Further analyses are required to disentangle the causes of unbalanced PG in the uterine lumen and to verify whether inadequate signalling transfer may cause detrimental downstream target effects. Reciprocal communication A recent analysis of transcriptome data of the Day 16 conceptus and corresponding endometrium attempted to identify specific ligands of embryonic origin and their respective receptors on the endometrium and, vice versa, endometrial ligands and their respective trophoblast receptors (Mamo et al. 2012). These pairs of possible interacting molecules provide a very suitable basis for targeted verification. To further discriminate necessary embryo–maternal communication from a background of ‘molecular noise’, SCNT pregnancies are a valuable model, as outlined below. During early gravidity, increased uptake of almost all amino acids (AA), foremost the essential AA, occurs in the uterine lumen (Groebner et al. 2011a). This is congruent with findings in sheep (Gao et al. 2009) and allows the evaluation of a critical supply of nutrients for the pre-attachment conceptus and pregnancy outcome. Essential AAs originate from the blood and are transported through the vascular wall and the endometrial tissue into the uterine lumen, supplying the gravid uterine horn with sufficient nutrients (Hugentobler et al. 2008). The fast-growing conceptus most likely induces the increase in AA-transporting processes via signalling molecules (Farin et al. 1990; Godkin et al. 1997) and/or increased blood flow in the uterine artery (Ford et al. 1979; Silva and Ginther 2010). By further investigating the composition of the respective uterine fluid, we found that the uterine lumen of SCNT pregnancies contained lower concentrations of specific essential AAs (Groebner et al. 2011c). For many components of the uterine fluid, as for PG mentioned earlier, it is not as easy to disentangle the endometrial from the embryonic contribution. However, essential AAs cannot be synthesised by the embryo, but are exclusively derived from the maternal circulation. Thus, in SCNT pregnancies, inadequate embryonic signalling must have led to an endometrial dysfunction resulting in a perturbed uterine milieu (Groebner et al. 2011c). With respect to the physiological increase in AAs, an undersupply may result in a negative impact on further embryonic development. This demonstrates that reciprocal interactions between the developing embryo and the endometrium occur.


Problems arising from disturbed embryo]maternal communication The embryo has been shown to be flexible towards the surroundings in which it develops. However, the impact of a developmentally important event may be small and only visible by applying an epigenetic perspective on early embryonic development. Epidemiological assessment of epigenetic programming in humans and other species has revealed that an unfavourable intrauterine environment influences the metabolic and endocrine constellation of the fetus (Hales and Barker 2001; Fleming et al. 2004; Jammes et al. 2011). A specific constellation may become critical if an unsuspected over- or undersupply of nutrition during critical windows of postnatal development prevails (Gardner et al. 2009). Because the application of most advanced technologies allows the quantification of the embryo’s responses to the environment, it appears that developing embryos are highly susceptible to the impact of exogenous stressors and changes at specific sensitive windows (Sinclair et al. 2010). One important sensitive window occurs around fertilisation and first embryonic cleavages before implantation, respectively. Here, global de- and remethylation waves take place that are specifically prone to environmental imprints (Reik 2007). During this phase, the embryo is located in the reproductive tract, specifically in the oviduct and the uterus. Maternal metabolic imbalances have been shown to affect the composition of the follicular fluid, which, in turn, reduces the developmental competence of the oocyte (Leroy et al. 2010, 2012). As described for other mammalian species, an altered nutrient composition of the uterine fluid due to the maternal constitution is likely (Seki et al. 2012). Thus, proteomic and metabolomic approaches are warranted that characterise normal and altered histotroph composition. The mechanisms by which external influences on the maternal side can lead to changes in the composition of the microenvironment of the female reproductive tract specifically regarding the uterine milieu need to be addressed. Finally, long-term consequences of an altered uterine environment must be assessed. For animal production, this could specifically include favourable conditions for later production traits (Sinclair et al. 2010). The prevailing task is to understand physiological signalling in the reproductive tract that is set within limits of physiological constraints. Challenging the embryo’s flexibility from the maternal side needs to ensure that the species-specific constraints prone to quality, quantity and timing of impact are known. Without this knowledge, interventions like supplemental feeding or in vitro culture conditions need to be revisited. Conclusion Maternal communication with gametes and embryos is a complex and continuous process. The deciphering of signals originating from the embryo and the endometrium provides exciting insights into the process of the establishment of pregnancy. However, it is a challenging task to disentangle players in a molecular twitter of fellow travellers. Despite major technological breakthroughs of –omics technologies, the precise biochemical mechanism for the induction of luteolysis, the synchronised intermission of cyclicity in case of pregnancy and the obligatory maternal support remain to be resolved. On the


one hand, the numerous lists of possible target genes must be read very carefully not to overlook unexpected key players. Appropriate bioinformatics tools must be developed to obtain as much information as possible from long lists of candidates from different experimental set-ups without the need for reduction of data. Additionally, a directed candidate gene approach has been proven to be an adequate way in which to approach functionality. For this, several different appropriate animal models must be carefully designed. A concerted effort is needed to unravel the underlying physiology behind the scene. Acknowledgements We greatly acknowledge the support of the German Research Foundation (FOR 478) and, in part, by the German Ministry for Education and Research (BMBF, FUGATO-plus, COMPENDIUM).

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