The oviduct as a complex mediator of ... - Wiley Online Library

REVIEW ARTICLE Molecular Reproduction & Development 77:934–943 (2010)

The Oviduct as a Complex Mediator of Mammalian Sperm Function and Selection WILLIAM V. HOLT1* 1 2

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ALIREZA FAZELI2

Institute of Zoology, Regent’s Park, London, UK Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Level 4, Sheffield, UK

SUMMARY The fallopian tube, or oviduct, is no longer considered merely a conduit that joins the uterine horns and the ovaries, being recognised as a venue for the capacitation of spermatozoa and fertilisation. However, recent evidence has implicated the oviduct in the stringent selection of spermatozoa prior to fertilisation, sperm storage prior to fertilisation, the regulation of sperm motility and possibly the guidance of spermatozoa towards the egg. Moreover, the arrival of spermatozoa within the oviduct is now known to regulate gene expression in oviductal epithelial cells with the consequent up- and downregulation of various proteins. In this review, we examine the emerging significance of sperm– oviduct interactions, as they relate to both physiological functions and the likelihood that the oviduct has a role in post-copulatory sperm selection by females (cryptic female choice) under conditions of sperm competition. The mechanisms by which sperm selection might operate still remain a mystery, especially when the underlying rationale for such mechanism appears to require the recognition by the female tract of sperm qualities related to the intrinsic integrity and information content of the sperm DNA. The oviduct not only selects against spermatozoa containing fragmented DNA but also imposes selection related to the fitness or quality of individual males. This implies the existence of, as yet unrecognised, mechanisms for the detection and interpretation of sperm-surface markers that link phenotypic and genotypic qualities of each individual cell. Mol. Reprod. Dev. 77: 934–943, 2010. ß 2010 Wiley-Liss, Inc. Received 4 April 2010; Accepted 22 July 2010

INTRODUCTION Over 300 years ago the physician, Regnier de Graaf, from Delft in the Netherlands described how he examined the ovaries and oviducts of a series of female rabbits at various intervals after mating (30 min, 6 hr, 24 hr and 27 hr, then at daily intervals up to 10 days and finally at 14 and 29 days; Jocelyn and Setchell, 1972). He commented that there was no trace of semen within the oviducts but realised that the eggs entered the oviducts after being released from the ovarian (Graafian) follicles, and eventually entered the uterine horns and developed into foetuses. Within the text of his description there is an implicit recognition that some semen

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[S]perm passage through the uterus and [uterine-tubule junction] is a selective process, and one where most spermatozoa fail to meet whatever are the appropriate criteria.

* Corresponding author: Institute of Zoology, Regent’s Park London NW1 4RY, UK. E-mail: [email protected]

Funded by the Higher Education Funding Council of England.

Published online 1 October 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mrd.21234

should probably have entered the oviduct and ‘‘moistened’’ the eggs. These experiments and observations were conducted about 100 years after the oviduct was described anatomically by Gabriele Fallopio, Professor of Anatomy, Surgery and Botany at the University of Padova in Italy (Thiery, 2009), hence the common usage of the name, fallopian tube, especially when referring to human anatomy. Although this historical background is well known, one reason for mentioning it now is to point out that our understanding of oviductal function has developed in a series of

Abbreviation: UTJ, uterine-tubule junction.

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steps. The earliest insights suggested that the oviducts initially act to capture the eggs upon their release from the ovarian follicles and provide a suitable venue for early embryonic development. Oviductal involvement in sperm functions, other than as a passive conduit, was not suspected until after the 1960s, once the importance of capacitation as an essential prelude to fertilisation had been discovered (Austin and Bishop, 1958; Chang, 1958). Although it became widely accepted that fertilisation could not proceed without capacitation (Bedford, 1983), the link between capacitation events and oviductal function remained unclear because a number of researchers showed that exposure to the uterine environment and to treatments outside the body (ovarian follicle contents, anterior chamber of the eye and artificial media containing enzymes such as b-amylase) could induce spermatozoa to penetrate oocytes. The critical role played by oviductal content in the induction of capacitation was demonstrated by Bedford and Shalkovsky (1967), who experimented with rabbit spermatozoa that had been sequestered within the rabbit uterus and oviducts and compared these with spermatozoa stored in the uterus of oestrous rats. In this study the homologous system was the more effective at inducing capacitation, and it was concluded that, at least, the final stages of capacitation occur within the oviducts and are species-specific. A simple search on Web of Science using the terms ‘‘spermatozoa’’ and ‘‘capacitation’’ revealed that 33 articles could be retrieved for the years 1961–1970 and 55 for the years 1971–1980. These were mainly concerned with demonstrating the phenomenon of capacitation itself, although some authors began to explore the biochemical basis of capacitation. This growth of interest appeared to cause some confusion of terminology in the literature, because Chang (1984) remarked in a review that, ‘‘It is proposed here that in order to save further confusion, capacitation of spermatozoa should be defined as originally proposed, that is, to include all the events that lead to the development of the capacity of mammalian spermatozoa to penetrate eggs. All the changes in the spermatozoa before hyperactivation and acrosome reaction should be defined as the first part of capacitation.’’ This all-inclusive definition of capacitation is significant in the context of this review because it firmly places ‘‘functional’’ capacitation, or in a sense, the ‘‘last’’ part of capacitation as occurring within the oviduct when the spermatozoa are situated within the immediate neighbourhood of the oocytes. In turn, this implies a significant physiological and biochemical role for the oviduct in the induction and control of events and processes once spermatozoa have traversed the utero-tubal junction (UTJ). The latest step forward in understanding oviductal function comes from the demonstration that the murine and porcine oviducts respond dynamically to the arrival of gametes and embryos by transcribing novel gene sequences and producing new proteins (Fazeli et al., 2004; Georgiou et al., 2005, 2007). Although the significance of these observations has yet to be appreciated, they certainly underline the active and responsive nature of the sperm– oviduct dialogue and eliminate any suggestion that the oviduct is only a conduit that joins the uterus to the ovaries.

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THE OVIDUCT AS A COMPLEX MEDIATOR OF SPERM FUNCTION Sperm–oviduct interactions that precede fertilisation by hours or a few days are undoubtedly influenced by the dynamics of the hormonal environment. In general, mating and natural insemination in most mammalian species only take place during a specific phase of the reproductive cycle. However, this generalisation shows many exceptions because many groups of species have evolved differences in their social mating systems and have developed mechanisms for the short- or long-term storage of spermatozoa within the uterus or oviduct (Holt and Lloyd, 2010). Most research studies have focused on model species that typically only mate when the female is receptive, usually a few hours to a few days before ovulation while circulatory oestrogen concentrations are increasing. This situation means that the sperm–oviduct interactions studied in species such as rats, mice, pigs and cattle are taking place within a hormonally dynamic environment that is not necessarily easy to reproduce in vitro. Conversely, this also means that those mammals that have evolved the ability to store spermatozoa for a few days, possibly associated with induced, rather than spontaneous, ovulation, must also have developed systems to prevent cell death by uncoupling it from capacitation. These preliminary considerations show clearly that the study of sperm–oviduct interactions has recently moved into a new era which is characterised by complexity. Species differences in reproductive behaviour are both governed by, and a product of, their different evolutionary pathways. These differences are in turn influenced by different hormonal environments and even by differences in the anatomy and physiology of insemination and sperm transport. In this review of sperm–oviduct interactions, we aim to keep this complexity in mind and to see whether or not it is helpful in understanding the biological processes that lead towards fertilisation.

SPERM TRANSPORT TO THE OVIDUCT In order for fertilisation to proceed naturally the spermatozoa must first enter the oviduct, via the narrow entrance known as the UTJ. Although this is a rather obvious statement, the process itself is more subtle and complex than might be imagined. Many studies have shown that despite the deposition of large numbers of spermatozoa into the vagina, cervix or uterus at the time of insemination, only a small proportion of those cells reach the oviducts (for reviews, see Eisenbach and Giojalas, 2006; Holt, 2009). In an experiment which involved the intravaginal insemination of rabbits with a controlled number of spermatozoa (100–150 million cells), Overstreet and Adams (1971) reported that they recovered about 400 spermatozoa by flushing the oviducts 13 hr after insemination. In the same study they also estimated that the uterine horns contained about 1 million spermatozoa, so the transfer rate from uterus to oviducts must have been about 1:10,000. This remarkable loss rate is mirrored in similar studies from other species. In their article, Overstreet and Adams (1971) not 935

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only estimated the proportion of spermatozoa reaching the oviducts, but also performed mixed inseminations with semen from pairs of rabbits, where the spermatozoa of one buck were marked with a fluorescent dye. This allowed them to estimate which of the bucks contributed most spermatozoa to the uterine and oviductal populations. This approach allowed them to demonstrate that about 80% of spermatozoa within the uterine horns 13 hr after insemination originated preferentially from one of bucks. Interestingly, they found that by 6 hr post-insemination there was no apparent preferential colonisation of the uterus; no oviductal spermatozoa were found at that point. The preferential colonisation of the uterus and oviducts noted in this study was correlated with highly skewed outcomes of mating experiments. These observations were difficult to explain at the time, and the authors considered explanations such as differential sperm lifespans, differential susceptibility to phagocytosis and differential loss rates of spermatozoa from the reproductive tract. With the benefit of hindsight, these experiments can now be seen as important in the context of studies in sperm competition and cryptic female choice, where the skewed outcomes of mixed inseminations in a variety of species (e.g., in pigs, Stahlberg et al., 2000; cattle, Stewart et al., 1974 and some marsupials, Taggart et al., 1998) are regarded as the product of processes with a strong influence on sexual selection and evolution (for review, see Gomendio et al., 1998). While the concept of sperm competition is relatively easily understood, especially when spermatozoa from pairs of males are inseminated in equal numbers and on one single occasion, the term ‘‘cryptic female choice’’ is more obscure and difficult. In essence it means that, even after copulation, females can exert some control over which male fathers her offspring when she mates with several males during a single fertile period (Birkhead, 1998; Telford and Jennions, 1998). It is notoriously difficult to be certain that cryptic female choice is operating, but in principle it is regarded as a process that can result from a female-controlled process or structure that selectively favours paternity by conspecific males with a particular trait. Structures within the female tract that act as barriers to impede the progress of spermatozoa, for example, the cervix, cervical mucus and the UTJ itself, could be regarded as functionally important and relevant to cryptic female choice mechanisms. These and other findings have raised the possibility that sperm passage through the uterus and UTJ is a selective process, and one where most spermatozoa fail to meet whatever are the appropriate criteria. The criteria might also include an element of chance because many spermatozoa may be too distant from the UTJ, but there is undoubtedly also a strong physiological influence controlling this process. One of the first hypotheses about the sperm selection process at the UTJ was derived from studies of the mouse t-haplotype (Olds-Clarke and Johnson, 1993; Olds-Clarke et al., 1996). This model has been reviewed extensively (Olds-Clarke, 1996) but in essence it concerns the wellestablished observation that sperm motility is severely compromised in homozygous mice, carrying t-haplotypes on both alleles of chromosome 17. In contrast, the heterozygous mice, which are identical in all other respects, produce

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spermatozoa with superior motility while wild-type spermatozoa show normal motility. Experimentally, it has been shown that spermatozoa from homozygous mice are virtually incapable of reaching the oviduct (Olds-Clarke, 1991), while spermatozoa from the heterozygotes are capable of entering the oviduct, but not to the same extent as the wild type. These relatively straightforward observations have recently been dissected in detail at the molecular level, again using mice, to discover the basis for these motility differences (Herrmann et al., 1999; Bauer et al., 2005, 2007), and have produced far-reaching results. The explanation involves complex interplay between different postmeiotically expressed components of the t-complex. Two tightly linked genetic factors, the T-complex transmission ratio distorters (Tcd) that cause abnormal flagellar function, and the T-complex responder (Tcr) which rescues the motile function in these flagellae and confers a selective fertilisation advantage to the t-haplotype spermatozoa (Herrmann et al., 1999), are responsible for the t/t male sterility. Importantly, these factors are expressed post-meiotically (Veron et al., 2009) in spermatids, and the transcripts are retained within individual spermatids rather than being shared among members of the post-meiotic syncytium. These authors noted that the relevant proteins were not expressed until very late in spermiogenesis, when the sperm tails were aligned near the luminal surface of the seminiferous tubules. They commented on the sophistication of this mechanism and suggested that it is highly likely to be a conserved process, responsible for non-Mendelian inheritance across species. Taking this argument a step further suggests that this mechanism could be important in sperm selection, sexual selection (whereby it might exert significant influence on sperm competition and cryptic female choice) and ultimately in the evolutionary history and future of a species. Entry to the oviduct is not, however, only governed by sperm motility differences. Extensive studies of mouse lines with disrupted genes for the family of proteins called ADAMs (A Disintegrin And Metallopeptidase domain) have revealed that besides being unable to participate in sperm–zona pellucida binding, the spermatozoa from some of the mouse lines (specifically those where calmegin, Adam1a, Adam2, Adam 3 and angiotensin converting enzyme (ace) are disrupted) are unable to enter the oviduct (Cho et al., 1998; Hagaman et al., 1998; Nishimura et al., 2004; Yamaguchi et al., 2009). The authors of these articles therefore concluded that sperm migration into the oviduct depends on specific interactions between the sperm surface and the UTJ. These findings emphasise that molecular integrity of the sperm surface is an essential qualification for traversing the UTJ and is consistent with earlier experimental outcomes in studies involving the direct insemination of capacitated or uncapacitated hamster spermatozoa into the two uterine horns of individual animals (Shalgi et al., 1992). Lower numbers of capacitated spermatozoa were able to enter the oviducts in these experiments. As capacitation changes the nature of sperm surface biochemistry, and even disturbs the ability of spermatozoa to attach to oviductal epithelial cells (Fazeli et al., 1999), it is not surprising that capacitated spermatozoa have reduced ability to enter the oviduct. The authors of this study interpreted their results in

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terms of the need for progressive motility to facilitate passage through the UTJ; however, it is also likely that the capacitation process disturbed the cell surface sufficiently to inhibit sperm entry to the oviducts. The requirement for a specific compatibility between the spermatozoa and the UTJ was also tested in an ingenious experiment where female hamsters were inseminated with both homologous spermatozoa and spermatozoa from other species (mouse, rat, guinea pig and rabbit; Smith et al., 1988). One hour after insemination, while many live hamster spermatozoa were found in the oviducts, relatively few of the heterologous spermatozoa had managed to reach the oviductal isthmus.

SPERM SELECTION AND THE OVIDUCT The previous discussion showed that those spermatozoa reaching the oviduct have undergone selection processes related to both their membrane biochemistry and their motility. In some species such as cattle, sheep and humans where ejaculates are deposited intravaginally, these spermatozoa may already have been selected by exhibiting superior performance in their ability to traverse cervical mucus (see, e.g., Cox et al., 2002). In other species with uterine semen deposition it may be that spermatozoa are partly selected by their ability to avoid phagocytosis by lymphocytes in the uterine horns. However, once within the oviductal environment they seem to be subjected to several further selection processes before being permitted to interact with oocytes. These interactions represent the products of refined evolutionary processes whose role seems to be the prevention of oocytes being fertilised by inferior quality spermatozoa. Various investigators have characterised some aspects of the superior sperm quality associated with oviductal binding; these include intact acrosomes (Gualtieri and Talevi, 2000); uncapacitated status in horse (Thomas et al., 1994), bovine (Lefebvre and Suarez, 1996) and pig (Fazeli et al., 1999); good sperm morphology in horse (Thomas et al., 1994); low internal calcium, reduced membrane protein phosphorylation (Petrunkina et al., 2001) and n et al., 2008) in the pig; superior high quality chromatin (Ardo motility and chromatin integrity in humans (Ellington et al., 1999) and superior volume regulation in the bovine (Khalil et al., 2006). In this sense the mammalian female reproductive tract is acting as a highly effective semen analysis laboratory that is capable of distinguishing between ‘‘good’’ and ‘‘excellent’’ sperm quality at the level of the individual spermatozoon. Currently, this level of discrimination is completely impossible to achieve within the laboratory, and certainly in advance of the fertilisation process itself. In addition to these screening processes, it is becoming clear that the oviduct is not passively acting as a mere conduit for the passage of spermatozoa and that a sperm–oviduct dialogue is established. The functional significance of this dialogue has yet to be established. In 1996, Hunter (1996) published a review of the factors that together might ensure that fertilisation of oocytes is accomplished in the presence of a low sperm/egg ratio. He cited a number of publications that described the avid binding of spermatozoa to the isthmic surface of the oviduct Mol Reprod Dev 77:934–943 (2010)

and then considered the mechanisms that might regulate the further progression of the spermatozoa towards the oocytes. A low sperm/egg ratio would certainly permit the most stringent of sperm selection processes to take place. A moment’s consideration makes it obvious that if spermatozoa outnumber the eggs by orders of magnitude, it would be extremely difficult to control the quality of the fertilising spermatozoon. Hunter’s (1996) suggestions for a low sperm/egg ratio could be split on the basis of three different modes of action. Firstly, the sperm reservoir within the oviductal isthmus would represent a means of delaying sperm transport, so that they could be released slowly by progesterone-dependent mechanisms. This mechanism has the advantage that progesterone concentrations in and around the oviductal isthmus might be determined by ovarian function. In this scenario the progesterone concentration might be correlated with the number of pre-ovulatory follicles. Secondly, Hunter suggested that molecular messages derived from the oocyte–cumulus complex might influence the release of spermatozoa and influence their passage towards the oocytes. The third control mechanism was suggested as involving molecular gradients within the oviduct that could influence sperm activity and their directional trajectories. More than a decade later, these suggestions are still valid although other processes have now joined the list and point towards the complexity of these interactions. The oxidation and reduction of thiol groups on the sperm surface has been proposed as an additional mechanism for sperm adhesion and release at the bovine oviductal epithelial surface (Talevi and Gualtieri, 2001, 2010; Talevi et al., 2007; Gualtieri et al., 2009, 2010). These authors have demonstrated the principle that cell–cell interactions in the oviduct can be switched on and off rapidly by sulphated glycoconjugates, thereby allowing sperm binding and release to be under physiological control. Sperm binding to the oviductal epithelium is also controlled by receptor-mediated interactions involving specific oligosaccharides. These interactions were noted at least 15 years ago (Demott et al., 1995; Satoh et al., 1995), and more recent studies have implicated them as modulators of capacitation (Sostaric et al., 2005; Taitzoglou et al., 2007) as well as sperm binding and release. In addition, a separate line of research has implicated a sperm binding globulin and the annexin family of proteins as important sperm-selective components of the porcine oviductal epithelium (Teijeiro et al., 2007, 2009). To complicate the picture further, it seems that sperm–oviduct binding interactions are also mediated via proteins that originate in the seminal plasma and are carried on the sperm surface after ejaculation (Gwathmey et al., 2003; EkhlasiHundrieser et al., 2005; Liberda et al., 2006; for review, see Talevi and Gualtieri, 2010). Such studies complement and explain previous observations that capacitation is associated with reduced ability to bind to the oviductal epithelia (Lefebvre and Suarez, 1996; Fazeli et al., 1999). Hunter’s prediction that progesterone is involved in the release of spermatozoa from the epithelium can now be combined with his third prediction as recent studies have implied that progesterone itself is an effective chemotactic agent for human spermatozoa (Oren-Benaroya

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et al., 2008; Publicover et al., 2008; Smith et al., 2009; Teves et al., 2009). Progesterone achieves its role as a chemoattractant by interacting directly with mechanisms controlling motility modulation within the oviduct, that is, activation of adenylyl cyclase stimulates intracellular cAMP production; this in turn stimulates a protein kinase cascade that acts directly on the flagellum to change the shape of the flagellar beat. The importance of this direct action on spermatozoa is perhaps more apparent in the light of other data showing that the oviductal environment tends to inhibit sperm motility (Overstreet and Cooper, 1975; Suarez et al., 1992; Satake et al., 2006; Suarez, 2008), albeit to an extent that seems to vary between species. Nevertheless, experiments underlining the importance of hyperactivated motility in enabling spermatozoa to escape the isthmic sperm reservoir in the mouse and move towards the oocytes present in the ampullar regions were undertaken approximately two decades ago (Suarez et al., 1991) and have recently been refined to reveal that if the motility activation pathway is intrinsically defective, for example, in the case of CatSper-null mutant mice (Ho et al., 2009), then neither hyperactivation nor oviductal transport can take place. Given the complexity of the sperm interactions with the reproductive tract, it is clear that there is considerable scope for differential responses between the individual spermatozoa, and hence for sperm selection. Evidence from a small but increasing number of studies suggest that two categories of sperm selection occur within the oviduct: (a) discrimination based on DNA integrity and (b) selection based on more subtle properties that reflect both the individual spermatozoon and the individual male that produced it. At first glance it is difficult to see how the female reproductive tract could recognise whether the DNA of an individual spermatozoon is intact or fragmented, given that there is a general recognition that DNA fragmentation is only weakly correlated with other sperm parameters such as motility and viability (Cohen-Bacrie et al., 2009; Gosalvez et al., 2009). Laboratory tests for DNA fragmentation are, by their nature, directed at the DNA itself rather than at some proxy of DNA quality located at the sperm surface. However, since it is well known that spermatozoa function within an environment that is finely balanced in terms of redox activity, and that oxidative stress is an important correlate of DNA damage (Agarwal et al., 2009; Shamsi et al., 2009; Thomson et al., 2009), it seems plausible that the sulphydryl-mediated sperm– oviduct binding interactions described by Gualtieri et al. (2009) could form the basis of a selection mechanism. As the binding mechanism relies on the oxidative status of disulphide bonds in molecules at the interface between the sperm and oviductal surfaces, inhibition of the reversing mechanism, which involves the reduction of disulphides to thiols, would prevent the release of individual spermatozoa. This suggestion is purely speculative but presents a hypothesis that could be tested. Whether or not this is a significant mechanism, recent studies have demonstrated the ability of the female reproductive tract to discriminate against spern et al., 2008; matozoa with damaged or unstable DNA (Ardo Hourcade et al., 2010). In a reflective review, Velando et al. (2008) developed a similar hypothesis, by which sperm

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selection operating both before and after copulation might be based around mechanisms that screen for oxidative damage. A further interpretation of ejaculate heterogeneity and complexity is that males may have evolved the rich diversity of sperm-based differences as a response to female tendencies to prevent all but the fittest genotypes from ever reaching the eggs. Theories of sperm competition and sperm selection are based on the premise that they represent a significant mechanism for evolution via Darwinian sexual selection. In mechanistic terms, most of the focus has been on the phenotypic and biochemical diversity of the spermatozoa; however, it is also likely that the female reproductive tract has evolved its own mechanisms for screening the genetic quality of the spermatozoa. For example, protein components of the zona pellucida (ZP2 and ZP3) are viewed as evolving under the influence of positive Darwinian selection, with the result that their amino acid sequences are subject to a greater rate of change than other, nonreproductive, proteins (Swanson et al., 2001). The multiple sophisticated and complex sperm selection mechanisms that exist are unlikely to be useful unless there is some correlation between the genetic complement of the individual spermatozoon and its own phenotype. If this were not the case, the selection process imposed by the female tract or the self-selection processes produced by sperm–sperm competition would have no merit in a genetic and evolutionary sense. Some of the evidence cited above, especially that from studies of mutant or knockout mice, demonstrates that such linkage does indeed exist, and that dysfunction in specific gene loci can result in failure to reach the oviduct or the oocyte. However, if sperm selection operates at a level governing the fitness and survival of the next generation, we also need to postulate that more complex correlations exist between the functionality of individual spermatozoa, their ability to reach and fertilise eggs, and the overall quality of their genetic payload. Some evidence for the existence of such mechanisms comes from two studies, both of which found evidence that human and mouse sperm–egg interactions are nonrandom and are subtly dependent upon their genotype at the major histocompatibility complex (MHC; Rulicke et al., 1998; Ziegler et al., 2002). The MHC-based mechanism is apparently highly conserved and operates across widely differing species. For example, it is known to influence sperm–egg interactions, even in externally fertilising salmon (Yeates et al., 2009), where competitive mating experiments showed that males won significantly greater fertilisation success when competing for eggs from females of the same MHC genotype. Previous studies involving the insemination of eggs by mixed sperm preparations from pairs of male salmon had demonstrated that fertilisation success was determined significantly by relative sperm velocity (i.e., the ratio of mean sperm velocity values of the two individuals; Gage et al., 2004), rather than sperm length or shape, thus implying that female MHC genotype can somehow affect sperm velocity itself. Odorant receptors have been implicated as important actors in the MHC recognition system, and both their existence in mammalian spermatozoa and their potential role as chemoattractants has been demonstrated (Vosshall, 2004; Neuhaus et al.,

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2006; Spehr et al., 2006). As with the suggested role of progesterone as a chemoattractant (Teves et al., 2009), the potential modulation of sperm motility is thought to depend on direct interactions with G protein-coupled receptors (Gibson and Garbers, 2000) and the signal transduction systems that control protein phosphorylations in the sperm flagellum. Capacitation is well known as a process that individual spermatozoa undergo prior to fertilisation. The process occurs asynchronously within a sperm population, thereby achieving the effect that a few spermatozoa are ready for fertilisation at any given moment over a prolonged period. This presents a problem for experimentalists interested in topics such as sperm selection and chemotaxis, because those spermatozoa responding to selective stimuli are probably always present as a tiny minority and therefore difficult to study. Chemoattraction studies in humans and mice have shown that possibly only 10% of the sperm population is chemotactically responsive (Eisenbach, 1999; Eisenbach and Giojalas, 2006). These are believed to represent the capacitated population (Fabro et al., 2002), which is also known to have undergone various two-dimensional reorganisations of the plasma membrane. By way of example, Spinaci et al. (2005) showed that the distribution of heat shock protein 70 (Hsp70) on the boar sperm surface changes during capacitation from a precisely defined region on the external surface of the equatorial segment to a more widespread distribution, and is probably also translocated from the inner to the outer leaflet of the plasma membrane. One reason for citing this particular example is that extracellular heat shock proteins are now recognised for their role in cell signalling pathways (Calderwood et al., 2007), where their functions may only be expressed once the heat shock proteins have become assembled into new molecular complexes. Similar topographical rearrangements of sperm plasma membrane antigens have been reported to occur before and during capacitation in other species (Jones et al., 1990; Topfer-Petersen et al., 1990; Nehme et al., 1993). Functionally, this means that some sperm selection mechanisms may only exist transiently, and in a small proportion of cells. Techniques that focus on the biology of single cells will almost certainly be required to understand the detailed mechanisms that link genetic and functional selection.

THE SPERM–OVIDUCT DIALOGUE Recent observations have revealed that the role of the oviduct prior to fertilisation is more complex than even the occurrence of capacitation and chemoattraction might suggest. In a relatively unassuming article published in 1993, Ellington et al. (1993) demonstrated that if cultured oviductal epithelial cells are co-incubated with spermatozoa, epithelial cells respond by the de novo synthesis of new proteins. This article was of particular interest as it showed clearly that the oviduct is not just a passive conduit but is instead an active participant in controlling the oviductal environment. Several follow-up studies in mice and pigs (Fazeli et al., 2004; Georgiou et al., 2005; Seytanoglu et al., 2008) have supMol Reprod Dev 77:934–943 (2010)

ported these findings and have advanced the study of oviduct–sperm interactions to a new level and a new paradigm, as the spermatozoa and epithelial cells must be engaging in mutual signal transduction interactions. Experiments in mice revealed that the delivery of spermatozoa into the reproductive tract by natural mating resulted in greater than twofold changes in the gene expression levels of 214 genes present on oligonucleotide arrays (Fazeli et al., 2004). The same patterns of gene modulation were not induced by infertile mice spermatozoa (T145H mice) that were able to produce seminal plasma but not spermatozoa. A subsequent in vivo experimental study conducted in pigs (Georgiou et al., 2007) showed that the arrival of spermatozoa into the oviduct caused the production of 19 proteins to be upregulated by more than twofold. This is compared with the upregulation of only three proteins by the presence of oocytes. These studies demonstrated that the gametes have the ability to perturb and modify their own environment, but examination of the list of upregulated proteins does not immediately suggest what the modifications achieve. Nevertheless, among the proteins identified, one in particular (oviduct-specific glycoprotein; OSG) stands out immediately as being significant in terms of its ability to boost fertilisation rate (Kouba et al., 2000; Buhi, 2002; McCauley et al., 2003) and also to control polyspermy (Coy et al., 2008). Several other possible functions of this upregulation in protein production have been suggested. These include the production of proteins that assist with the survival of live spermatozoa (e.g., heat shock proteins; Boilard et al., 2004; Lachance et al., 2007; Lloyd et al., 2008, 2009; Elliott et al., 2009) and the destruction and removal of dead spermatozoa (complement family of proteins; Georgiou et al., 2007), in addition to preparing the oviduct for the imminent arrival of embryos.

SYNTHESIS AND CONCLUSIONS In this short review we have aimed to demonstrate how research over the last two decades has transformed our understanding of sperm–oviduct interactions. Sperm selection mechanisms have been studied in considerable detail from different perspectives, and it has become clear from the elaborate mechanisms devoted to this function alone that there must be considerable merit in preventing all but a small number of spermatozoa from accessing the oocytes. Evolutionary biologists have published many studies supporting the concept that postcopulatory ‘‘cryptic female choice’’ involves a recognition that sperm quality somehow reflects the overall fitness of a male and predicts the fitness of his offspring (Birkhead and Pizzari, 2002; Hosken et al., 2003), but the mechanisms by which this could be achieved have remained obscure. Our increased understanding of oviductal function is beginning to furnish suitable explanations. It is noticeable that most of the information about sperm– oviduct interactions has been gained through studies of a remarkably small subset of mammalian species (rabbit, mouse, hamster, sheep, pig, cow, horse and human). While these, mainly by coincidence, represent different branches

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of mammalian evolution, they cannot be said to represent much diversity in terms of social mating systems and their reproductive consequences. For example, the rabbit is the only species on the list that ovulates in response to mating (induced ovulation). Does this imply that the gamete-induced changes in oviductal gene expression and protein production might differ markedly from observations thus far in the mouse and in pigs? Marsupials have received very little attention with respect to sperm–oviduct interactions; only two species (the tammar wallaby, Macropus eugenii, and brushtail possum, Trichosurus vulpecula, having been investigated; Sidhu et al., 1999a,b). Within a few hours of binding, the wallaby spermatozoa appeared to undergo capacitation as evidenced by the re-alignment of the sperm head to a new position perpendicular to the main flagellar axis. This remarkable change in morphology is not mirrored by any eutherian mammal species thus far examined; moreover, the co-culture system and its very obvious endpoint should theoretically provide an unusually versatile model system for further experimentation. The bats are a further group of mammals that show some highly unusual adaptations in terms of sperm–oviduct interactions. Some of these species are capable of storing spermatozoa within the uterus or oviduct for about 6 months, from the time of mating in the autumn until the females ovulate in the spring after the winter hibernation. Although extensive studies describing these interactions have been published (Racey et al., 1973; Crichton et al., 1993; Hosken, 1997) very little progress has been made towards understanding the mechanisms involved. Extremely intimate cellular associations form between spermatozoa and oviductal epithelial cells (Racey et al., 1987) and it is highly likely that the sperm–oviduct dialogue is far more active than in most other species. However, none of the more recent physiological insights into sperm–oviduct interactions had been investigated in these species until very recently, when Roy and Krishna (2010) demonstrated that the alignment of sperm heads towards the oviductal epithelium is associated with increased circulating testosterone, the presence of androgen binding protein within epithelial glands and the presence of androgen receptor at the site of sperm storage. These authors hypothesised that long-term sperm storage might be mediated via nongenomic androgen actions. There is an important literature about the nongenomic action of androgens and it is inappropriate to dwell on it here. However, it may be significant that the nongenomic actions involve the control of cell metabolism and cytoplasmic signalling pathways via G protein-coupled receptors, in ways that bear some similarities to the pathways controlling sperm motility activation and chemoattraction (Michels and Hoppe, 2008). There is currently considerable interest in generalising the sperm–oviduct interaction mechanisms in order to develop an ‘‘interactome map’’ and produce ‘‘in silico’’ models that can be interrogated and tested without the use of animals and cells. These are important aims of an international project (COST Action FA0702 Gemini) currently supported by the European Union (http://www.cost-gemini.eu/ index.html). It is nevertheless clear from the observations above that species differences currently limit our ability to

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understand the entire field. We need to establish more clearly to what extent there is common ground between species and whether different processes have evolved and evolved again separately, even though they aim to achieve the same ends. Given time, it should therefore be possible to refine the in silico models with species-specific detail. However, to achieve this objective we need to increase the breadth of this field by studying species that may not apparently be of immediate economic or clinical interest. Unfortunately, this comparative approach is not usually seen as worthy of major grant funding, even though the case for support is unarguably important and journals welcome the opportunity to publish the outputs. A recent review in this journal (Wildt et al., 2009) presented this argument at length and with considerable eloquence, having first analysed the reproductive biology literature from 1999 to 2009. The authors found that only 5.9% of the articles published in that decade addressed the >97% of mammalian species that could be considered ‘‘nontraditional’’ (i.e., anything other than human, cow, pig, sheep, goat, horse, domestic buffalo, dog, cat, rabbit, mouse, rat, hamster, guinea pig, gerbil, macaque, monkey or baboon). These species represent a huge experimental resource that is currently overlooked yet may hold the key to many of the remaining puzzles in the science of reproductive biology.

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