Roles of the oviduct in mammalian fertilization

in Reproduction
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  • 1 Departments of Physiology, Cell Biology and Histology, Department of Veterinary and Animal Sciences, Faculty of Veterinary

The oviduct or Fallopian tube is the anatomical region where every new life begins in mammalian species. After a long journey, the spermatozoa meet the oocyte in the specific site of the oviduct named ampulla and fertilization takes place. The successful fertilization depends on several biological processes that occur in the oviduct some hours before this rendezvous and affect both gametes. Estrogen and progesterone, released from the ovary, orchestrate a series of changes by genomic and nongenomic pathways in the oviductal epithelium affecting gene expression, proteome, and secretion of its cells into the fluid bathing the oviductal lumen. In addition, new regulatory molecules are being discovered playing important roles in oviductal physiology and fertilization. The present review tries to describe these processes, building a comprehensive map of the physiology of the oviduct, to better understand the importance of this organ in reproduction. With this purpose, gamete transport, sperm and oocyte changes in the oviductal environment, and other interactions between gametes and oviduct are discussed in light of recent publications in the field.

Abstract

The oviduct or Fallopian tube is the anatomical region where every new life begins in mammalian species. After a long journey, the spermatozoa meet the oocyte in the specific site of the oviduct named ampulla and fertilization takes place. The successful fertilization depends on several biological processes that occur in the oviduct some hours before this rendezvous and affect both gametes. Estrogen and progesterone, released from the ovary, orchestrate a series of changes by genomic and nongenomic pathways in the oviductal epithelium affecting gene expression, proteome, and secretion of its cells into the fluid bathing the oviductal lumen. In addition, new regulatory molecules are being discovered playing important roles in oviductal physiology and fertilization. The present review tries to describe these processes, building a comprehensive map of the physiology of the oviduct, to better understand the importance of this organ in reproduction. With this purpose, gamete transport, sperm and oocyte changes in the oviductal environment, and other interactions between gametes and oviduct are discussed in light of recent publications in the field.

The spermatozoon in the oviduct

Arrival, binding to, and releasing from epithelial cells

Depending on the species, the sperm are deposited in different sections of the female tract. In a large number of mammals, the semen is ejaculated into the anterior vagina during coitus (e.g. cows, sheep, rabbits, primates, dogs, and cats). In others, sperm are placed in the cervix (e.g. sows) or directly spurted into the uterus (horses and many rodents). Regardless of where the sperm is initially dropped, to encounter the oocyte, the sperm is required to go through the uterotubal junction and enter the oviduct.

However, not all the ejaculated spermatozoa reach this initial portion of the oviduct. Once ejaculated, most sperm are eliminated from the female tract by different mechanisms (Yanagimachi 1994). A very low percentage of the sperm population is able to reach the ampulla or the ampullar–isthmic junction, and a recent work using genetically modified mice models has shown that a critical step in sperm transport is their migration through the uterotubal junction (Tokuhiro et al. 2012). Although the molecular basis of this transport is not well understood, it has been observed that knockout models with deficiencies in this transport are infertile. Presently, analysis of sperm from eight different knockout mice has shown problems in uterotubal junction transport. The null mice models presenting this phenotype include those for Ace (Hagaman et al. 1998), Adam1a (Nishimura et al. 2004), Adam2 (Cho et al. 1998), Adam3 (Shamsadin et al. 1999), Calr3 (Ikawa et al. 2011), Clgn (Ikawa et al. 1997), Tpst2 (Marcello et al. 2011), and Pdilt (Tokuhiro et al. 2012). It is interesting that all these models appear to converge in the lack of ADAM3; therefore, it has been hypothesized that this molecule is central to uterotubal transport and the other knockout models presenting this phenotype are involved in the process and regulation of ADAM3.

Once in the isthmus, the spermatozoa are bound to the ciliated epithelial cells. This process seems to be mediated by carbohydrate residues present in the oviductal epithelial cells and lectin-like proteins on the sperm head (Suarez 2002). The molecules involved in this process vary among species (Talevi & Gualtieri 2010). In hamsters, sperm binding to oviductal epithelium is mediated by sialic acid (DeMott et al. 1995) and by galactose in horses (Dobrinski et al. 1996). In pigs, galactosyl and mannosyl residues seem to be involved in sperm–oviduct binding (Ekhlasi-Hundrieser et al. 2005). In cattle, strong evidence supports the involvement of fucose residues that are recognized by spermadhesin BSP1 (also called PDC-109) (Ignotz et al. 2001, Gwathmey et al. 2003, Sostaric et al. 2008), and in llamas (camelid), N-acetylgalactosamine and galactose have been observed that inhibit the sperm binding to the oviductal cells (Apichela et al. 2010).

From the sperm side, several proteins have been shown to have carbohydrate-binding affinities and could then interact with the epithelial cells. Thus, it was previously reported that the spermadhesins AQN1 and AWN bind to the sequences Galβ1,3GalNAc and Galβ1,4GlcNAc (Dostàlovà et al. 1995, Calvete et al. 1996). AQN1 also bind to mannose residues (Ekhlasi-Hundrieser et al. 2005) and, in the bovine species, spermadhesin BSP1 is able to recognize fucose residues (Gwathmey et al. 2003).

Independent of the specific carbohydrate residues or the lectin-like proteins participating in the adhesion, the role of the oviduct in such sperm–epithelial cell interaction seems to be the formation of a sperm reservoir. The more plausible explanation for the formation of a sperm reservoir in different species of mammals is the sequential releasing of sperm to allow only a small quantity of them reaching the oocyte at any given time and therefore reducing the possibility of polyspermy (Hunter & Léglise 1971, Hunter 1973). Interestingly enough, the sperm release is modulated by the female estrous cycle with increased activity observed during the periovulatory period (Suarez 2008b) and it is probably related to the existence of unknown signaling between the recently attached cumulus–oocyte complex (COC) and the oviductal cells (Kölle et al. 2009) and with the progesterone (P4) levels (Bureau et al. 2002).

Although the mechanisms responsible for sperm release are not well understood, it seems that the number of carbohydrate binding sites present in the oviductal epithelium surface is not greatly affected (Suarez et al. 1991, Lefebvre et al. 1995, Baillie et al. 1997). However, it has been proposed that this release is correlated with capacitation events (Smith & Yanagimachi 1991, Lefebvre & Suarez 1996). On the one hand, sperm release could be due to a loss of proteins involved in binding the sperm to the oviduct. As an alternative possibility, as part of the capacitation process, hyperactivation of the sperm motility might play an important role allowing these cells to escape the attachment by shear force (Demott & Suarez 1992, Pacey et al. 1995). Even though, it cannot be discarded that both mechanisms are coordinated to free the sperm from the epithelium, but additional hypothesis is also emerging.

Due to the complex protein composition found in the oviductal fluid (Avilés et al. 2010, Mondéjar et al. 2012a), two additional mechanisms could contribute to the regulation of the sperm oviductal interaction. First, activities for different glycosidases have been detected in the oviductal fluid showing variations along the estrous cycle (Carrasco et al. 2008a, 2008b). These enzymes could act on the specific carbohydrate residues present in the epithelial cells necessary for the sperm binding and contribute to the release of the sperm from the reservoir. Supporting this model, it is important to point out that the best characterized sperm–oviductal interaction was described in the bovine model (Fig. 1). In this species, it was reported that sperm protein BSP1 recognizes specifically the fucose residues contained in the annexin present at the oviductal epithelium (Hung & Suarez 2010). Thus, fucosidase activity, present in the oviductal fluid (Carrasco et al. 2008b), could contribute to the regulation of the binding. Additionally, the presence of annexin in the oviductal fluid (Mondéjar et al. 2012a) could also participate in such regulation, as the atypical secretion of this protein has been reported previously (Christmas et al. 1991).

Figure 1
Figure 1

Mechanism for the sperm binding and releasing from the oviduct in the bovine model. (a) Sperm binding is mediated by lectin-like protein as BSP1 present in the sperm plasma membrane that recognizes fucose contained in the annexin molecule bound to the epithelial cell membrane. (b) Sperm binding to the oviduct could be modulated by two different mechanisms that can act at the same time. (b1) Annexin present in the oviductal fluid compete for the BSP1 binding site present on the sperm. (b2) Fucosidase enzymes present in the oviductal fluid can remove fucose residues contained in the annexin present in the oviductal epithelium. (c) These different mechanisms and the development of hyperactivative motility allow the sperm release from the oviductal reservoir.

Citation: REPRODUCTION 144, 6; 10.1530/REP-12-0279

Secondly, as mentioned earlier, AWN has the ability to bind to carbohydrate residues. Unexpectedly, it was reported that this protein is secreted by the epithelial cells in the swine oviduct (Song et al. 2010) and, consequently, could compete with the sperm for oviductal carbohydrates suggesting its participation in the sperm-releasing process. Additional experiments are necessary to confirm these different hypotheses. The development of improved experimental conditions as the use of labeled sperm, video microscopy, and the in vitro system culture for oviductal epithelium will bring more light about the molecular mechanisms involved in the sperm–oviduct interaction (Miessen et al. 2011).

Capacitation

As explained earlier, it has been hypothesized that release of the sperm from the oviductal epithelium is due to their capacitated state (Smith & Yanagimachi 1991, Lefebvre & Suarez 1996). Discovered independently by Austin (1951) and Chang (1951), capacitation has been defined as those physiological events that render the sperm able to fertilize. Discovery of capacitation was fundamental to allow development of IVF. First demonstrated in rabbits in 1959 (Chang 1959), this technology led to the first test-tube baby in 1978 when Mary Louise Brown was born (Steptoe & Edwards 1978). This success was recognized in 2010 when Dr Roberts was awarded the Nobel Prize in Medicine. Although the initial experiments by Chang and Austin were conducted using artificial insemination in live female rabbits, most of what it is known about this process is derived from in vitro experimentation. In vitro capacitation in most mammalian species is achieved by incubation of the sperm in a simple media that mimic the oviductal milieu. In particular, capacitation-supporting media requires bicarbonate, calcium, energy sources, and serum albumin as a cholesterol-binding compound.

One critical change in the sperm-surrounding milieu after ejaculation is the change in HCO3 concentration (Fig. 2). This anion plays a role in the regulation of the cAMP pathway (Visconti et al. 2011) through the stimulation of a unique type of adenylyl cyclase present in sperm, known as soluble adenylyl cyclase (SACY; Buck & Levin 2011). SACY knockout mice are sterile (Hess et al. 2005, Xie et al. 2006) and their sterility phenotype is mapped to a lack of capacitation; in particular, sperm from the SACY null mice are not able to move actively and cannot hyperactivate (Hess et al. 2005). Consistent with the role of cAMP in capacitation, a similar phenotype is observed when the testis-specific protein kinase A (PKA) catalytic subunit splicing variant is eliminated by homologous recombination. Using sperm of these mice in vitro, the authors clearly showed that PKA is required for the activation of flagellar beat and for the flagellar waveform asymmetry associated with hyperactivation (Nolan et al. 2004). In addition to genetic approaches, the role of cAMP in the regulation of sperm is also supported by biochemical and pharmacological approaches. Inhibitors of PKA such as H89 and rpScAMP and peptides that disrupt PKA binding to anchoring proteins block sperm motility and IVF (Visconti et al. 1995, Vijayaraghavan et al. 1997). Downstream of the activation of a cAMP/PKA pathway, capacitation in vitro is also associated with an increase in protein tyrosine phosphorylation (for review, see Visconti et al. (2011)). Despite the fact that many groups have shown similar regulatory pathways in sperm from other species, there is still a limited knowledge on the identity and the role of proteins phosphorylated during capacitation.

Figure 2
Figure 2

Model for the regulation of sperm capacitation. Removal of cholesterol by BSA modulates the influx of HCO3 and Ca2+. These ions regulate the activity of the sperm-soluble adenyl cyclase (SACY), increasing intracellular cAMP, and activating PKA. The activation of cSrc family kinase sensitive to both SU6656 and SKI606 downregulates a ser/thr phosphatase, which modifies the phosphorylated steady state of PKA substrates. As a consequence, the onset of PKA phosphorylation is followed by the promotion of tyrosine phosphorylation associated with sperm capacitation. Okadaic acid is a known ser/thr phosphatase inhibitor and can induce some of the capacitation-associated processes.

Citation: REPRODUCTION 144, 6; 10.1530/REP-12-0279

Although it is believed that the regulation of signaling pathways in vitro mimic those happening in vivo, this possibility has not yet been demonstrated. Activation of PKA occurs immediately upon ejaculation, once the HCO3 concentration surrounding the sperm milieu increases from low millimolar levels in the cauda epididymis to ∼25 mM concentration in the semen and female tract fluids. However, tyrosine phosphorylation and hyperactivation are not believed to occur until the sperm reach the oviduct.

As mentioned earlier, most of what it is known about the signaling events controlling sperm capacitation was obtained from in vitro experiments. While these observations are important, they do not address how the female tract controls the speed of capacitation and delivers freshly capacitated sperm to the ovulated eggs. The assumption that capacitation is regulated by the same signaling pathways in vivo as in vitro, although logical, has not yet been tested. Studies of in vivo capacitation are more complex because of the more difficult access to the sperm and also because of the smaller quantity of cells that can be obtained. Because of these limitations, novel approaches should be developed. Among them, the analysis of phosphorylation pathways could be performed by immunofluorescence analysis using anti-phospho antibodies such as anti-phospho PKA substrate or anti-phosphotyrosine antibodies (Krapf et al. 2010). Some of the challenges presented by these experiments are i) that these experiments should be conducted in static fixed sections which would not allow following the fate of the signaling changes in live sperm and ii) that sections could cut the sperm in planes not compatible with anti-phospho staining making it difficult to quantify the level of phosphorylation. Despite these perceived problems, this approach has the advantage that it does not need a lot of material as in the case of western blots used in most in vitro experiments. In addition, sections of oviducts have been used successfully to visualize fluorescent mouse sperm in the oviduct (Tokuhiro et al. 2012), and confocal microscopy or even multiphoton microscopy can be used to optically assess thick sections of oviduct to provide more complete and clear images of different sperm compartments. Alternatively, it is predicted that the use of genetically modified mice in which fluorescent markers of capacitation are inserted through transgenic technology would allow investigating how the sperm behaves in vivo. This technology has been used to observe the acrosome reaction (AR) using sperm in which the green fluorescent protein is targeted to the acrosomal compartment (Nakanishi et al. 1999).

Sperm hyperactivation

The oviduct takes care of and modifies the sperm in such a way that it is able to fertilize. One of these modifications is the sperm pattern motility.

Sperm within the epididymis are unmotile or poorly motile (inactivated). When they are released from the epididymis and mixed with the seminal plasma, they become activated. The term ‘activated motility’, described by Yanagimachi (1994), means that the sperm start to swim straight and vigorously with symmetrical flagellar beats. Once the activated sperm are in the female tract after mating, only a small population (hundreds to thousands) will be able to reach the oviduct and become established in the sperm reservoir (described earlier). Spermatozoa in this storage place are attached and stabilized during the preovulatory interval with suppressed motility and intact surface membranes (for review, see Hunter (2012)), but later sperm will detach acquiring another motility pattern named ‘hyperactivated motility’ (Fig. 3a). This condition was defined for the first time by Yanagimachi (1970) who observed that hamster sperm in the oviduct had a very vigorous motility pattern with high amplitude and asymmetrical flagellar beating. In the years following that discovery, it was demonstrated that the ‘hyperactive motility’ is essential for the sperm to fertilize. So, this term was redefined as the swimming pattern shown by most sperm retrieved from the oviductal ampulla at the time of fertilization (Suarez & Ho 2003).

Figure 3
Figure 3

Roles of the hyperactivation induced by the oviduct on the sperm during the approach to the oocyte: (a) detaching of the sperm from the epithelial cells, (b) transport to the fertilization site, (c) cross through cumulus cells, and (d) penetration of zona pellucida.

Citation: REPRODUCTION 144, 6; 10.1530/REP-12-0279

But, when do mammalian spermatozoa become hyperactivated? One of the known triggers is the increase in intracellular Ca2+([Ca2+]i) (Publicover et al. 2008). This is probably prompted by ovulation and is a consequence of P4 secretion influencing the oviduct epithelium (for review, see Hunter (2012)) and helping sperm transport to the fertilization place (Chang & Suarez 2012). And, how is Ca2+ mobilized into the cytoplasm to induce hyperactivation? Spermatozoa require Ca2+ channels in the plasma membrane, which have been identified and named as CATSPER1 (CATSPER) proteins (CATSPER1–4), located in the principal piece of the flagellum (Kirichok et al. 2006, Qi et al. 2007). In fact, several reports have shown that male mice null mutant for Catsper1 genes are infertile (Ren et al. 2001, Quill et al. 2003, Jin et al. 2007, Qi et al. 2007), suggesting that the reason is the lack of hyperactivation in the spermatozoa of these animals (Ren et al. 2001, Quill et al. 2003). Ho et al. (2009) supported this hypothesis because spermatozoa from Catsper-null mutants did not detach from the epithelium or show deep asymmetrical flagellar bending. As indicated earlier, P4 could be involved in sperm detachment (Bureau et al. 2002) and hyperactivation. It is known that P4 rises [Ca2+]i levels in human sperm (Publicover et al. 2007) but it is not known by which mechanism. Recently, Lishko et al. (2011) and Strünker et al. (2011) explained the action of this hormone on human spermatozoa where the P4, in combination with an elevation of intracellular pH, activates the CatSper channels involved in Ca2+ human sperm intake. The extracellular pH increase in oviductal fluid during estrus could possibly be the primary factor for inducing hyperactivation in the oviduct, activating CatSper and raising intracellular pH (Suarez 2008a). HCO3 levels could play an important role for this purpose.

Summarizing the oviductal influence on spermatozoa physiology, an increasing body of research suggests that periovulatory changes in pH, temperature, [Ca2+], and HCO3 levels in the oviductal fluid modulate different aspects of sperm function, including releasing from the epithelial cells, membrane modifications leading to capacitation, and the hyperactive motility that addresses them to the oocyte vicinity (Hunter & Nichol 1986, Rodriguez-Martinez et al. 2001, Rodriguez-Martinez 2007, Coy et al. 2010, Zumoffen et al. 2010, Kumaresan et al. 2012).

The oocyte in the oviduct

Arrival to the fertilization site

The role of the oviduct on the oocyte transport has been classically attributed to the cilia beating and smooth muscle activity, speeded up by estrogens and slowed down by P4, when administrated in adequate dosages and times (Chang 1966). This principle is still valid, and modern video microscopy and biochemical techniques have contributed to describe the process in detail.

From studies in hamsters, the importance of the cumulus cells and the extracellular matrix of the COC on the picking up and initial adhesion to the infundibulum cilia was shown. Slight changes in the level of COCs expansion affected the initial adhesion and made their further transportation difficult (Talbot et al. 2003). Cilia that cover the exterior surface of the infundibulum beat in the direction of the ostium induce a current of oviductal fluid and move the COC into the oviduct. It was suggested in mice and humans that the P4 receptor, localized in the lower half of the motile cilia of oviduct ciliated epithelial cells, may directly regulate ciliary beat frequency (Teilmann et al. 2006), thus confirming the initial discoveries by Chang (1966).

Although it is a key factor, ciliary beating alone cannot provide the propulsive force behind oocyte movement along the oviduct. Spontaneous contractions of the oviduct are also necessary, and interstitial cells of Cajal associated with the smooth muscle cells along the entire length of the oviduct are responsible for electrical slow-wave events that couple in a one-to-one relationship with phasic contractions of the myosalpinx (Dixon et al. 2009). Dixon et al. demonstrated that these slow waves are not initiated by neural inputs, but they are driven by pacemaker activity provided by the oviductal cells of Cajal.

Another interesting body of research about oviductal motility and oocyte transport is that concerning the role of nitric oxide synthases (NOS). Lapointe et al. (2006) showed in the bovine oviduct that expression of inducible NOS is selectively upregulated by estradiol during the temporal window of oocyte transport. As NO plays a role as a relaxing agent in mammalian oviduct and its inhibition accelerates oocyte transport (Perez Martinez et al. 2000), regulation of NOS by estradiol suggests a fine-tuned equilibrium of the oviductal motility. Such equilibrium seems to be reached by nongenomic pathways of estradiol action including estradiol bound to its receptors, activation of cAMP, and partial participation of PKA (Orihuela et al. 2003) that again confirm Chang's discoveries.

Oocyte's changes in the oviduct

Once in the ampulla, transported by the cilia beating and smooth muscle contractions, the COC remains attached to the epithelium for a variable period of time. While previous in vivo studies in the pig model indicated that unfertilized oocytes reached the ampullar–isthmic region within 30–45 min from the beginning of ovulation (Hunter 1974) and that spermatozoa met them in this site, digital video microscopical studies in the cow oviduct have suggested that as soon as the mature COCs enter the ampulla, they are immediately firmly attached to the oviductal epithelium (Kölle et al. 2009). Whether inter-specific differences between the pig and cow or methodological differences between the experiments (in vivo in the pig and ex vivo in the cow) explain this controversy remains elusive.

One important change for the oocyte at this time is related to the removal of its investments: in some species, such as cows and sheep, cumulus cells are rarely detected around recently ovulated oocytes, whereas in primates and in pigs cumulus cells and oocytes are immersed in a dense plug (Hunter 1989). Even in this case, the plug is dissolved in the porcine species a few hours later and oocytes collected from the oviduct become naked within 1 h (Coy et al. 1993). However, a general consensus exists, based on wide experimental evidence, about the improving of the fertilization rates in most mammalian species in the presence of cumulus cells (Campos et al. 2001, Zhuo et al. 2001, Van Soom et al. 2002), underlying the importance of a rapid response of the oviduct, releasing the sperm from the reservoir, as soon as the oocyte arrives surrounded by the cumulus.

During the process of cumulus expansion and disaggregation, zona pellucida (ZP) becomes more accessible to the oviductal fluid permitting its modification by different molecules. Differences in ZP among oviductal and follicular oocytes, or zona maturation, have been referred by a number of authors, most of them related to changes at the ultrastructural level (Funahashi et al. 2001) and a few of them identifying specific molecules in the oviductal ZP that are not present in the ovarian ZP. Among them, oviduct-specific glycoprotein (OVGP1), osteopontin, and lipocalin-type prostaglandin D synthase were demonstrated to associate with the bovine ZP (Goncalves et al. 2008). Moreover, OVGP1 and heparin-like glycosaminoglycans (GAGs) from the oviductal fluid have been demonstrated in the pig and cow to participate in the functional modification of the ZP that, before fertilization, makes it more resistant to enzymatic digestion and to sperm penetration, contributing to the control of polyspermy (Coy et al. 2008). This mechanism is represented in Fig. 4. Finally, there is also a significant change in the sugar moieties of glycoproteins in the ZP following ovulation (Avilés et al. 1996, Aviles et al. 1997, El-Mestrah & Kan 2001), although the specific role of these changes needs to be investigated. Studies completing the list of proteins and sugars binding to the ZP in the oviduct could contribute to the comprehension of the molecular events affecting the sperm–oocyte interaction and to the definitive description of a model assigning to each molecule its specific role in this complex mechanism.

Figure 4
Figure 4

Pre-fertilization ZP hardening (adapted from Coy & Avilés (2010)). 1) When the oocyte is shedding in the ampulla soon after ovulation, oviduct-specific glycoprotein (OVGP1) surround it in a ‘shell’ 2) that is responsible for the ZP resistance to proteolysis. 3) Heparin-like GAGs in the oviduct fluid stabilizes and reinforces the binding of OVGP1 with ZP, which determines the interaction of selected spermatozoa 4) with such a modified ZP. 5) In the transit toward the uterus, the system is destabilized and OVGP1 is partially unbound or internalized. 6) Thus, ZP in the embryo reaching the uterus returns to the low resistance to proteolysis showed by the ovarian oocyte in (1).

Citation: REPRODUCTION 144, 6; 10.1530/REP-12-0279

Oocyte–sperm–oviduct interactions

Oviductal influence on the initial sperm approach to the oocyte

Once the sperm are hyperactivated and released into the oviduct, how do the sperm know which direction to travel in order to reach the oocyte? The sperm in the reservoir (Fig. 3a) are like ‘the boats docking in a port’…  they are attached, but when they are released (‘sailing on the sea’) they need a guide (‘navigator’) to reach the objective that in the sperm's case is the fertilization place. Thermo- and chemotaxis have been defined, in terms of fertilization, as the process by which sperm are guided by a temperature gradient (cooler to warmer; for review, see Eisenbach & Giojalas (2006)) or by a chemical gradient (Chang & Suarez 2010) to reach the oocyte. There are only a few studies about the motility on mammalian sperm responses to these gradients. Some substances have been identified as potential chemoattractants; for example, the P4 that is released during the ovulation (present in follicular fluid) and is produced by the cumulus cells that surround the oocytes (Chang & Suarez 2010). It has been postulated that [Ca2+]i increases during sperm chemotaxis (i.e. P4) induce turning swimming with asymmetric flagellar bending (for review, see Yoshida & Yoshida (2011)). Other components in oviductal fluid have been identified as chemoattractant, that is, the case for natriuretic peptide precursor, that modifies the sperm pattern motility and enhances [Ca2+]i levels, whose receptor has been recently shown in mouse spermatozoa (Bian et al. 2012). Temperature also seems to play a role in the levels of [Ca2+]i. Temperature stimulation activates the release of the internal sperm Ca2+ store affecting flagellar bending (Bahat & Eisenbach 2010). In addition to chemo- and thermotaxis, other factors as the movement of oviductal fluid, oviductal contractions, oviductal epithelium, and the internal structure of the oviduct (Burkitt et al. 2012) could also influence the sperm transport and guidance, although the evidence of these aspects has not yet been demonstrated in vivo.

After the sperm are hyperactivated and guided to the oocyte, they have to propel themselves through the viscous glycoprotein secretion in the oviduct toward the ampullar–isthmic junction (Fig. 3b). During the preovulatory stage, the mucus within the oviduct is extremely viscous before ovulation and may contribute to the suppression of sperm motility (Hunter et al. 2011); after ovulation, it become less viscous which would facilitate an adequate flagellar beat and progression of spermatozoa toward the ampulla (Suarez & Dai 1992, Hunter et al. 2011). Suarez & Dai (1992) showed an increase in flagellum propulsion when mouse sperm was confronted with an increase viscosity gradient medium. So, it seems that spermatozoa escape from the viscous fluid thanks to the hyperactivation. The flagellar beating during hyperactivation has been widely reported in vitro, but only a few experiments show the flagellar behavior simulating real conditions. Recently, Chang & Suarez (2012) have recorded mice sperm in the oviduct in conditions very close to in vivo. These authors showed a different motility pattern called anti-hook instead of pro-hook beating (amplitude of the bend in the same orientation as the hook of the head) described before in in vitro situations. The cause of these differences could be found (among other factors) in the composition (mucoid type) and viscosity of the oviductal fluid that are absent in most of the in vitro media used, making the sperm to propel themselves (better than to swim) in such a semisolid environment.

What seems to be obvious it is that sperm are exposed to a different microenvironment (viscosity, chemical agents, temperature, etc.) in their travel through the oviduct and they are continuously re-adapting their pattern motility to these conditions. As suggested by Brenker et al. (2012), CatSper could function as a polymodal translator for the chemical and physical code of each microenvironment into Ca2+ patterns to reach the site of fertilization.

Once the sperm reach the oocytes, they have to cross the cumulus cells surrounding them (Fig. 3c). Sperm GPI-anchored surface hyaluronidases and hyperactivated sperm motility are thought to be sufficient for the sperm to get through the cumulus (for review, see Yin et al. (2009)). Carrasco et al. (2008a, 2008b) have described some hexosaminidases in oviductal fluid (as it has been indicated in ‘Arrival, binding to, and releasing from epithelial cells’ section), which could be responsible for cumulus cell disaggregation from ovulated oocytes helping the sperm to cross this barrier. In addition, it was previously reported that SPAM1 (with hyaluronidase activity) is secreted by the oviduct and consequently can participate in the cumulus oophorus dispersion (Griffiths et al. 2008). Preliminary data from our laboratory also described the presence of the SPAM1 in the porcine and bovine oviduct (Acuña et al. 2011).

Moreover, in the latest reports, AR has also been observed during the sperm pass through the cumulus (Yin et al. 2009, Jin et al. 2011). Indeed, as Yanagimachi (2011) pointed out recently, the place where AR begins in mammalian sperm before fertilization has been a controversial topic. On one side of the debate, some researchers think that the AR takes place while the sperm advance through the cumulus, while on the other side, other scientists think that AR occurs on the surface of the ZP. On combining information from the latest reports, what seems to be clear is that the ZP may not be the only site of AR; therefore, cumulus cells play an important role in sperm AR. Among the potential chemoattractants, it is interesting to note that P4 secreted by cumulus cells is known to induce or promote the AR of spermatozoa of various species, but the spermatozoa in the oviduct are acrosome-intact or occasionally reacted (for review, see Sun et al. (2011)). The reason that the sperm in the oviduct are not reacted by P4 action is probably due to its concentration; the possibility is that sperm stimulation by low levels of P4 (μM–mM) does not induce AR (Publicover et al. 2008; Fig. 5). Gahlay et al. (2010) using transgenic mice (ZP2Mut and ZP3Mut) suggested that sperm binding at the surface of the ZP is not sufficient to induce sperm AR. In fact, Jin et al. (2011) recorded that the spermatozoa beginning the AR before reaching the zona were able to penetrate it. A new protein called NYD-SP8 has been recently identified in the cumulus–sperm interaction triggering Ca2+ mobilization and P4 release from cumulus cells inducing the AR (Yin et al. 2009). It should be noted that no one has ever followed a single spermatozoon from the beginning of the AR until the end of fertilization, so the exact place where fertilizing spermatozoa begin their AR and what triggers the AR remain to be determined (Yanagimachi 2011).

Figure 5
Figure 5

Progesterone (P4) levels close to the fertilization location and its effect on sperm. (A) Low P4 levels acting like a chemoattractant driving the sperm toward the oocyte. (B) High P4 levels secreted by cumulus cells induce acrosome reaction.

Citation: REPRODUCTION 144, 6; 10.1530/REP-12-0279

All the described steps related to the sperm modifications since they are ejaculated are probably addressed to enable them to bind and penetrate the extracellular matrix of the oocyte, the ZP (Gadella 2010). This is the last barrier before gamete fusion (Fig. 3d). Although the true mechanism is still unclear, and it is not the objective of the present review to describe the different models proposed for the sperm–ZP binding in the different species, it has been hypothesized that the sperm penetration through the ZP is dependent either entirely or partly on the mechanical force that provided the hyperactivated sperm (Kim et al. 2008). In fact, when hyperactivation was blocked in hamster sperm bound to the ZP, they were unable to penetrate it (Stauss et al. 1995) and, in this sense, hyperactivation induced by the oviduct can be considered as one more role of this organ in the fertilization process.

Does the oviductal fluid has any effect on fertilization itself?

Apart from its roles on the female and male gamete preparation for their meeting, discussed earlier, the question about the specific function of the oviduct or their secretions on the fertilization process itself, once the spermatozoon has bound to ZP, has not received significant attention in the research literature. Until recently, no molecules present in the oviductal fluid, other than OVGP1, already mentioned as a molecule reducing the number of sperm bound to ZP (Coy et al. 2008), had been demonstrated to directly affect the fertilization but new information is coming out every day supporting this hypothesis.

First, quantification of activity for five glycosidases in the oviductal fluid, with changes along the estrous cycle, has brought about different proposals, such as the possible role of oviductal hexosaminidase in the sperm–ZP binding, hydrolyzing the β-N-acetyl-glucosamine moieties at ZP (Carrasco et al. 2008b). Oviductal β-d-galactosidase could also regulate the sperm binding sites present in the ZP, as β-galactosyl residues in the ZP oligosaccharides have shown to be involved in porcine sperm–egg binding (Yonezawa et al. 2005). Further studies are necessary to describe the specific function of each glycosidase in the oviduct.

Secondly, plasminogen, a serum zymogen mainly produced by the liver, has also been quantified in the oviductal fluid and demonstrated to bind oocytes at ZP and oolemma level (Mondéjar et al. 2012b). Moreover, the different components of the plasminogen–plasmin system, including activators and inhibitors, are present in the oviduct and a model has been proposed by which, upon sperm contact to the oolemma, plasminogen activators are released from the oocyte (Fig. 6) and increase the conversion of the plasminogen into plasmin; such plasmin seems to remove spermatozoa attached to the ZP, thus contributing to the regulation of sperm penetration in the oocyte (Coy et al. 2012).

Figure 6
Figure 6

Proposed model for the role of the plasminogen–plasmin system during fertilization. Plasminogen and plasminogen activators are present in the oolemma and ZP of the oocyte (A1). Oocyte immunostaining with antibodies against plasminogen activators shows the oolemma strongly labeled (B1). When the spermatozoa bind the oolemma, plasminogen activators are released and increase the activation of the plasminogen into plasmin. Plasmin detaches additional spermatozoa bound to ZP (A2). The labeling in the oolemma decreases a few minutes after sperm binding (B2).

Citation: REPRODUCTION 144, 6; 10.1530/REP-12-0279

Finally, attention must be paid to recent studies about changes in the oviductal secretory proteome and transcriptome induced by the arrival of oocytes or spermatozoa to this organ (Fazeli et al. 2004, Georgiou et al. 2005). It seems clear that gametes modulate their own microenvironment and it can be anticipated that in the immediate future new molecules of oviductal origin participating in the fertilization process will be identified. Data from the whole oviductal transcriptome in different animal models and at the different phases of the estrous cycle would be very useful to complete the puzzle of the molecular pathways playing a role in the beginning of a new life (Mondéjar et al. 2012a).

Concluding remarks

A number of molecules participating in the oviductal signaling affects different steps in the fertilization process, including sperm binding and releasing from the oviductal epithelium, sperm capacitation and hyperactivation, oocyte oviductal maturation and pre-fertilization ZP hardening, sperm–ZP binding, and fertilization itself. Although descriptive genomic and proteomic studies have identified a high amount of candidate molecules participating in these processes (Fazeli et al. 2004, Georgiou et al. 2005), functional data are now necessary to understand the specific role of each molecule in each pathway. Only with these studies could be reached a significant advance in the comprehension of the fertilization process and, consequently, novel tools to modulate it, could be developed.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by grants AGL2009-12512-C02-01-02 from the Spanish Ministry of Science and Innovation and FEDER (to P Coy, F A García-Vázquez, and M Avilés) and grants HD38082 and HD44044 from the National Institutes of Health (to P E Visconti). P Coy, F A García-Vázquez, and M Avilés are members of the COST Action GEMINI FA0702.

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    Mechanism for the sperm binding and releasing from the oviduct in the bovine model. (a) Sperm binding is mediated by lectin-like protein as BSP1 present in the sperm plasma membrane that recognizes fucose contained in the annexin molecule bound to the epithelial cell membrane. (b) Sperm binding to the oviduct could be modulated by two different mechanisms that can act at the same time. (b1) Annexin present in the oviductal fluid compete for the BSP1 binding site present on the sperm. (b2) Fucosidase enzymes present in the oviductal fluid can remove fucose residues contained in the annexin present in the oviductal epithelium. (c) These different mechanisms and the development of hyperactivative motility allow the sperm release from the oviductal reservoir.

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    Model for the regulation of sperm capacitation. Removal of cholesterol by BSA modulates the influx of HCO3 and Ca2+. These ions regulate the activity of the sperm-soluble adenyl cyclase (SACY), increasing intracellular cAMP, and activating PKA. The activation of cSrc family kinase sensitive to both SU6656 and SKI606 downregulates a ser/thr phosphatase, which modifies the phosphorylated steady state of PKA substrates. As a consequence, the onset of PKA phosphorylation is followed by the promotion of tyrosine phosphorylation associated with sperm capacitation. Okadaic acid is a known ser/thr phosphatase inhibitor and can induce some of the capacitation-associated processes.

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    Roles of the hyperactivation induced by the oviduct on the sperm during the approach to the oocyte: (a) detaching of the sperm from the epithelial cells, (b) transport to the fertilization site, (c) cross through cumulus cells, and (d) penetration of zona pellucida.

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    Pre-fertilization ZP hardening (adapted from Coy & Avilés (2010)). 1) When the oocyte is shedding in the ampulla soon after ovulation, oviduct-specific glycoprotein (OVGP1) surround it in a ‘shell’ 2) that is responsible for the ZP resistance to proteolysis. 3) Heparin-like GAGs in the oviduct fluid stabilizes and reinforces the binding of OVGP1 with ZP, which determines the interaction of selected spermatozoa 4) with such a modified ZP. 5) In the transit toward the uterus, the system is destabilized and OVGP1 is partially unbound or internalized. 6) Thus, ZP in the embryo reaching the uterus returns to the low resistance to proteolysis showed by the ovarian oocyte in (1).

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    Progesterone (P4) levels close to the fertilization location and its effect on sperm. (A) Low P4 levels acting like a chemoattractant driving the sperm toward the oocyte. (B) High P4 levels secreted by cumulus cells induce acrosome reaction.

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    Proposed model for the role of the plasminogen–plasmin system during fertilization. Plasminogen and plasminogen activators are present in the oolemma and ZP of the oocyte (A1). Oocyte immunostaining with antibodies against plasminogen activators shows the oolemma strongly labeled (B1). When the spermatozoa bind the oolemma, plasminogen activators are released and increase the activation of the plasminogen into plasmin. Plasmin detaches additional spermatozoa bound to ZP (A2). The labeling in the oolemma decreases a few minutes after sperm binding (B2).

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