Alternative models for the study of embryo - maternal cross-talk and signaling molecules from fertilisation to implantation

Abstract

In nature, mammalian life is conceived inside the female genital tract, more specifically in the oviduct. Because the processes of fertilisation and early preimplantation development take place in one of the most inaccessible parts of the mammalian body, it has been studied predominantly in vitro. In static culture platforms, the environmental conditions to which the gametes and embryos are exposed are in sharp contrast to what is observed in vivo. In this Research Front on embryo–maternal interactions, we present four reviews that investigate model systems for the study of embryo–maternal cross-talk and the processes that are known to be important in the period between fertilisation and implantation. The Research Front is one of the outcomes of a European Union-funded COST (European Cooperation in Science and Technology) Action on ‘Maternal Interaction with Gametes and Embryos’ (FA0702; http://www.cost-gemini.eu, accessed 20 September 2011), which aims to promote understanding of this topic by bringing together researchers to share data from different species. In the female reproductive tract, embryos are surrounded by a constantly changing minimum amount of media and are constantly moved by ciliated epithelia. The preimplantation embryo, in vivo, develops in the absence of direct cell contact with the reproductive tract before implanting. It is free-floating, lacks a blood supply and is dependent on luminal secretions of the oviduct and uterus for its nutrition. The preimplantation embryo expresses several receptors for signalling ligands (O’Neill 2008). These signalling ligands are often paracrine factors, defined as factors that are secreted by one cell type and that execute their function on another cell type. They can originate from cells of the reproductive tract (e.g. cytokines) and have an effect on the embryo, or can be secreted by the embryo and have an effect on the oviduct or uterus (Orsi and Tribe 2008). It is clear that these paracrine factors are crucial in the embryo–maternal dialogue. The importance of normal embryo–maternal interaction is evidenced by the finding that exposure of ruminant embryos to a suboptimal environment can lead to the so-called large offspring syndrome: affected offspring show changes in phenotype, such as having twice to five times increased birthweights. In many cases breathing difficulties, reluctance to suckle and sudden perinatal death can occur and the severity of the syndrome is influenced by culture conditions and animal species (Farin et al. 2010). In humans, assisted reproduction has been associated with increased risk of imprinting diseases such as Beckwith– Wiedemann syndrome (Owen and Segars 2009). Abnormal development originates from epigenetic changes in imprinted genes and epigenetically sensitive alleles (for review, see Jammes et al. 2011), and hypothetically this can be caused by exposure to unwanted signalling molecules during a potential window of vulnerability in development. These cases of abnormal embryonic, fetal and neonatal development illustrate the pressing need to understand what happens at the time of fertilisation and during the first days and weeks of life. What is the best approach to study these signallingmolecules and in which species should they be studied? If we first focus on the species, it seems that the mouse has traditionally been the most popular model specific for the human (or even for mammals in general). This is based on the fact that mice are highly productive (reaching sexual maturity early (6–8 weeks) and producing many offspring per litter). They exhibit a similar placentation to humans (i.e. hemochorial) (Rosenfeld 2010). However, for studying signalling molecules in connection with embryo–maternal interactions, the mouse may not be the best choice after all. Most mouse strains are inbred, genetically almost identical and therefore not comparable to humans, which are markedly diverse, with genetic and epigenetic variability. Moreover, the mouse genome is dissimilar from that of humans, in that the number of unique orthologous groups is greater for rodents than for several othermammalian species includingman (Hansen 2010). In this respect, farm animals – such as cattle, pigs and even horses – are a much more interesting group of model species for research in (human) reproduction, especially when one wants to focus on signalling ligands. Another important recent development is that the advancement in molecular tools has led to the complete sequencing of the genomes of cattle (Larkin 2011), pigs (Fan et al. 2011) and horses (Chowdhary and Raudsepp 2008). The horse represents a valuable model for human infertility for several reasons: (1) breeding sport horses is often postponed to later ages, and this is associated with reduced fertility, both in mares and stallions, (2) such breeding horses can successfully be treated with intracytoplasmic sperm injection and embryo CSIRO PUBLISHING