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Asian J Androl. 2011 January; 13(1): 88–96.
Published online 2010 November 1. doi:  10.1038/aja.2010.74
PMCID: PMC3739399

Cellular mechanisms regulating sperm–zona pellucida interaction

Abstract

For mammalian spermatozoa to exhibit the ability to bind the zona pellucida (ZP) they must undergo three distinct phases of maturation, namely, spermatogenesis (testis), epididymal maturation (epididymis) and capacitation (female reproductive tract). An impressive array of spermatozoa surface remodeling events accompany these phases of maturation and appear critical for recognition and adhesion of the outer vestments of the oocyte, a structure known as the ZP. It is becoming increasingly apparent that species-specific zona adhesion is not mediated by a single receptor. Instead, compelling evidence now points toward models implicating a multiplicity of receptor–ligand interactions. This notion is in keeping with emerging research that has shown that there is a dynamic aggregation of proteins believed to be important in sperm–ZP recognition to the regions of sperm that mediate this binding event. Such remodeling may in turn facilitate the assembly of a multimeric zona recognition complex (MZRC). Though formation of MZRCs raises questions regarding the nature of the block to polyspermy, formation and assembly of such a structure would no doubt explain the strenuous maturation process that sperm endure on their sojourn to functional maturity.

Keywords: capacitation, fertilization, spermatozoa, sperm–zona pellucida interaction

Introduction

Defining the molecular mechanisms that underlie the species-specific interaction(s) between a fertilizing spermatozoon and the zona pellucida (ZP) has been a challenge that after more than 30 years of solid investigation has still not been overcome.1, 2, 3, 4 Gaining a thorough understanding of these mechanisms would aid in tackling the dual problems of explosive population growth in developing countries, and the increasing incidence of infertility throughout many developed countries.

The world population is estimated to reach seven billion by early 2012.5 Alarmingly, the majority of this population growth is occurring in developing countries where it is being driven, in part, by an unmet need for family-planning resources. Indeed, a recent analysis by the Global Health Council has indicated that of the 205 million worldwide pregnancies per year, as many as 30–40%, are unplanned.6 These statistics relay the inadequacy of current contraceptive measures and thus highlight the need for new approaches to contraception. By virtue of its specificity and susceptibility to suppression in both males and females, sperm–ZP interaction represents an attractive target for contraceptive development. The realization of such technology is, however, predicated on our ability to gain a comprehensive understanding of the mechanisms that underpin this fundamental interaction. Such knowledge would have the added benefit of helping to elucidate the reasons behind the paradoxical increase in the incidence of unexplained male factor infertility in developed nations. Reliable estimates suggest that as many as 17% of the couples in these countries currently take recourse to assisted reproductive technologies in an attempt to counter the problem of infertility.7 Furthermore, in ~40% of these cases, a specific, but generally poorly defined, male factor is believed to be the underlying cause.8

This review explores our current understanding of the mechanisms that underpin sperm–ZP interaction. Consideration is given to well-established paradigms of receptor–ligand interactions with an emphasis on emerging evidence for models involving the participation of multimeric receptor complexes and the maturational events that promote their assembly.

Maturation of mammalian spermatozoa

Spermatogenesis

To gain the functional competence to bind the ZP of an ovulated oocyte, spermatozoa must first undergo three distinct phases of maturation, namely, spermatogenesis, epididymal maturation and capacitation (Figure 1). Spermatogenesis is an intricate, exceptionally complex process that occurs in the male testis and is responsible for the production of large numbers of spermatozoa. During this process, spermatids undergo a dramatic morphological transformation from a rounded shape into an elongated cell consisting of a number of unique highly specialized regions: a head comprising the acrosomal vesicle, nucleus, cytoskeletal structures and cytoplasm; a midpiece which houses the mitochondria; and a flagellum that is used for locomotion. The majority of these changes occur during the final phase of cytodifferentiation, spermiogenesis, and are accompanied by protamine packaging of the DNA. Significantly, this latter event also results in silencing of the sperm's transcriptional machinery9, 10, 11, 12, 13.

Figure 1
Schematic representing the distinct changes in sperm surface architecture throughout the three stages of sperm maturation. Spermatogenesis, occurring in the testis, comprises the sequence of cell divisions and immense morphological alterations that convert ...

Epididymal maturation

Although spermatozoa that leave the testes are morphologically mature, they are still functionally incompetent, lacking both the capacity for forward progressive motility and the ability to bind the ZP14. These attributes are progressively acquired as the cells traverse the highly convoluted male reproductive tract or epididymis. The epididymis is a single duct that is generally subdivided into three broad anatomical regions: the caput (head) region, an adjoining corpus (body) region and the cauda (tail) region that terminates in the vas deferens. As mammalian spermatozoa progress from caput to cauda, they undergo distinct morphological refinement together with a series of biochemical alterations, ultimately producing cells that harbor both the potential for forward progressive motility and capacity for fertilization.15, 16, 17, 18 In most mammalian species, the potential to bind the ZP is first exhibited in the proximal corpus region, before reaching maximal levels in spermatozoa from the cauda region.18, 19, 20

One remarkable feature of this functional transformation is that it is not intrinsically driven. Indeed, owing to the exceptionally compact state of the spermatozoon genome, transcription is silenced and the balance of evidence suggests that the cells also remain translationally quiescent throughout their post-testicular maturation.21 Modifications to sperm architecture therefore appear to be stimulated by the complex intraluminal milieu in which the spermatozoa are bathed as they pass through the epididymal tubule.22 Among the more overt changes accompanying this period of maturation are remodeling of the sperm plasma membrane through the exchange and/or modification of a myriad of key lipids and proteins.23, 24, 25, 26 Although the molecular basis of these events and their contribution to the acquisition of ZP-binding affinity remain to be fully elucidated, they are temporally correlated with the appearance of two distinct subsets of macromolecular structures within the epididymal lumen: membrane-bound, prostasome-like epididymosomes27, 28, 29 and molecular chaperone-laden ‘dense bodies'.30 Emerging evidence suggests that these entities juxtapose with the sperm plasma membrane and potentiate the bulk transfer of proteins, including a subset implicated in sperm–oocyte interactions, to the sperm surface.31, 32

Capacitation

Notwithstanding the functional transformation of spermatozoa that accompanies epididymal maturation, the cells do not realize their full potential for fertilization until after ejaculation whereupon they undergo a final stage of maturation termed ‘capacitation'.33, 34, 35 Capacitation is stimulated as the cells ascend the female reproductive tract and is characterized by distinct biochemical and biophysical changes that act to modify the sperm surface, alter the intracellular pH and stimulate a number of integrated signal transduction pathways.36, 37, 38 A key correlate of the latter events is the dramatic upregulation of tyrosine phosphorylation across a large number of target proteins. This has in turn been causally linked to the attainment of a hyperactivated pattern of motility, recognition and adhesion of the ZP, and the ability to undergo acrosomal exocytosis (reviewed by Ref. 39).

For the purpose of this review, focus will be placed on the mechanisms that culminate in the ability of sperm to engage in interaction with the ZP (Table 1). Furthermore, as this is a cell surface-mediated event, discussion will be centered upon the capacitation-associated pathways that mediate sperm surface remodeling. One of the most well-documented events in this regard is a substantial efflux of cholesterol from the sperm plasma membrane that occurs during the initial stages of sperm capacitation.40 This efflux appears to be driven by active sequestration upon exposure to cholesterol sinks41, 42, 43 and is therefore reasoned to produce a more permeable plasma membrane in which the lateral movement of integral membrane proteins can occur more readily.44 Bovine serum albumin is commonly used within in vitro capacitating media to act as a cholesterol acceptor although an analogous acceptor is believed to be present within the female reproductive tract. Indeed, studies utilizing tritiated thymidine sterols and human follicular fluid indicate the high-binding efficiency of follicular fluid albumin for cholesterol.42

Table 1
Specific biochemical- and molecular-based changes that occur within mammalian spermatozoa during capacitation and underpin the acquisition of the ability to engage in sperm–egg interactions

At present, it remains unclear whether this large cholesterol efflux precedes or acts in concert with changes induced by the bicarbonate ion (HCO3).45, 46, 47, 48 In addition to its vital role in the initiation of key signaling processes, HCO3 has itself been shown to have a more direct role in sperm surface remodeling via stimulation of phospholipid scrambling.49, 50 Such scrambling destroys the characteristic membrane asymmetry, as distinct phospholipids are randomly ‘flip-flopped' across the bilayer. This redistribution of phospholipids has been theorized to be a prerequisite for cholesterol efflux,51 thus rendering the sperm membrane fusogenic and responsive to ZP glycoproteins.52

Cholesterol efflux may also be preceded by loss of inhibitory molecules, known as decapacitation factors (DFs), from the sperm surface. These factors originate predominantly in the epididymis and accessory organs, and their removal from populations of non-capacitated spermatozoa results in a rapid increase in fertilizing ability.53 A range of DFs have been characterized in eutherian mammals such as HongrES1,54 DF glycoprotein55 and phosphatidylethanolamine-binding protein 1.56 Recently, an additional DF, NYD-SP27, has been identified in human spermatozoa that is not derived from epididymal secretions, but is instead intrinsic to the spermatozoa.57

A further modification that appears to be tied to capacitation-associated cholesterol efflux is a polarized coalescence of proteins and lipids that reside within specialized plasma membrane domains termed as ‘lipid rafts'. Lipid rafts are generally defined as small, heterogeneous domains that serve to compartmentalize cellular processes,58 regulate the distribution of membrane proteins, and promote the activation of receptors and triggering of downstream signal cascades.59, 60, 61, 62 A widely used method to isolate lipid rafts exploits the detergent-resistant nature of the ‘raft' region, and thus these domains are often referred to as detergent resistant membranes.63 Lipid rafts will be discussed in more detail further in this review. What is important to note, however, is that the aggregation of these microdomains within the apical head region is believed to be very important for imbuing sperm with the ability to bind the glycoprotein ligands of the ZP.

Structure, function and biochemistry of the ZP

The ZP is a porous extracellular matrix that surrounds mammalian oocytes, ovulated eggs and embryos until the blastocyst stage of development.64, 65, 66, 67 It is composed of a small number of glycoproteins that are held together via non-covalent bonds to form long, interconnected fibrils. In mice, the ZP comprises three major sulfated glycoproteins-designated mZP1 (200 kDa), mZP2 (120 kDa) and mZP3 (83 kDa). In addition to orthologues of these three proteins (hZP1 (100 kDa), hZP2 (75 kDa) and hZP3 (55 kDa)), the human ZP comprises a fourth glycoprotein, hZP4 (65 kDa);68, 69 however, expression of the homologous protein in the mouse does not occur owing to a Zp4 pseudogene being present.39, 69, 70 Current evidence suggests that the mouse ZP is a non-covalently assembled structure composed of ZP2–ZP3 dimers that polymerize into filaments crosslinked by ZP1.71, 72 Furthermore, each of these ZP glycoproteins is heterogeneously glycosylated with asparagine-linked (N-) and serine/threonine-linked (O-) oligosaccharides, which also display varying degrees of sialylation and sulfation.

The initial interaction between spermatozoa and the ZP is loose and relatively non-specific.73 It is, however, rapidly followed by a significantly tighter binding that is largely species-specific and mediated by complementary receptor/ligand molecules expressed on the surface of the spermatozoa and ZP, respectively. Pioneering experiments performed by Bleil and Wassarman74, 75, 76 using crudely purified native ZP demonstrated that it is ZP3 that acts as both the primary sperm ligand, preferentially binding the plasma membrane overlying the acrosome of acrosome-intact sperm, and also acts as an acrosome reaction inducer during fertilization. For instance, purified mouse ZP3 competitively inhibits binding of mouse spermatozoa to mouse eggs in vitro.74, 77 In contrast, both ZP1 and ZP2 lack this inhibitory activity. Instead, ZP2 appears to act as a secondary ligand that, by virtue of its ability to bind to the inner acrosomal membrane, is involved in securing the adhesion of acrosome-reacted sperm and subsequently triggers events that are important for the prevention of polyspermy.75, 78 Such findings have since been validated by the generation of elegant transgenic models to study ZP function. These studies have provided overwhelming support for the importance of ZP3 in mediating primary sperm–oocyte interaction in the mouse. Indeed, female mice bearing a null mutation for ZP3 are completely infertile.79

Despite decades of investigation, the molecular basis of mammalian sperm–ZP3 recognition remains controversial. Prevailing evidence indicates that this interaction is most likely mediated by an intricate functional interplay between ZP3 carbohydrates and lectin-like proteins located on the sperm head.80, 81 Indeed, a variety of monosaccharides, complex carbohydrate moieties and lectins have been shown to effectively block the tight binding of spermatozoa from a number of mammalian species (including human) to homologous ZP3.82, 83, 84, 85, 86, 87, 88, 89 The most widely, although not universally, accepted model of primary sperm–ZP3 has been developed from studies of mouse models, and emphasizes the importance of O-linked carbohydrate moieties located near the carboxy terminus of the ZP3 glycoprotein.90, 91, 92, 93, 94 Evidence in support of this model has been advanced by the demonstration that complete deglycosylation or selective removal of O-linked oligosaccharides eliminates the ability of ZP3 to interact with spermatozoa.91 Furthermore, the O-linked oligosaccharides released by these procedures bind directly to spermatozoa and competitively inhibit their ability to adhere to the ZP.91 However, the bioactive components of the complex O-linked oligosaccharide ligand(s) that furnish the ZP3 protein remain to be unequivocally established and are the subject of ongoing debate.95 This controversy has recently been intensified by the production of transgenic mice bearing single or multiple null mutations for key glycosyltransferases that generate many of the O-glycans normally found in the zona.96, 97, 98 Remarkably, such mice produce oocytes that retain the ability to be fertilized. These results may therefore suggest a role for alternate carbohydrate moieties that furnish ZP glycoproteins in sperm recognition and binding. Indeed, murine ZP3 has been shown to exhibit high mannose and complex-type N-glycans.95 Further to this, it should be noted that not all mammalian species exhibit complete dependency on the O-linked oligosaccharides for sperm–ZP binding. For instance, in species such as the pig, there is evidence to suggest that N-linked neutral carbohydrate chains of the ZP3 orthologue appear to mediate its sperm receptor activity.99, 100 Furthermore, current evidence has also suggested that N-linked glycosylation of ZP3 may have a more significant role in human sperm–ZP binding, compared with O-linked glycosylation.101

Among the carbohydrate-independent sperm–ZP models that have been proposed, a small number of studies have suggested that this interaction may be facilitated, at least in part, by the core polypeptide backbone of ZP3.77, 102, 103 Notably, phenotypic analysis of a number of transgenic mouse models has also raised the prospect that the three-dimensional structure of the zona matrix, rather than a single protein (or carbohydrate), may be central in mediating sperm binding.81, 104, 105 Furthermore, it has also been suggested that before interaction with ZP3 ligands, spermatozoa are tethered to the ovulated oocyte via adhesion to a distinct glycoform of the high molecular weight, oviduct-specific glycoprotein that coats the ZP and perivitelline space.106, 107

Primary sperm–ZP interaction

The original model of primary sperm–ZP adhesion portrayed a relatively simple, single receptor–ligand interaction. This in turn provided the impetus for fervent, large-scale searches for ‘the' putative sperm receptor molecule. The ensuing research identified a range of molecules as potential instigators of this species-specific binding event and some of the more promising of these candidates will be briefly discussed here.

The ability of enzymes to elicit substrate-specific catalysis makes them ideal candidates for the initial binding between sperm and the ZP. A range of enzymes have been suggested, with the support of significant experimental evidence, to mediate this interaction. Owing to the large number of potential candidates, only a selected few will be briefly introduced. These include glycosyl enzymes, such as β-1,4-galactosyltransferase (GalT1),108, 109, 110 fucosyltransferase-5111 and α-d-mannosidase.112 For many years, GalT1 was favored as the most likely ZP3 receptor protein due in part to its ability to bind N-acetylglucosamine residues on ZP3, although being present as an integral plasma membrane component expressed upon the anterior region of the sperm head.108, 109 Interestingly, however, the generation of GalT1-null mice did not reveal the expected infertile phenotype but rather a subfertile one,113 thereby providing some of the first convincing evidence for functional redundancy among the putative ZP receptor candidates.

Lectins are a range of proteins that are defined as having a high affinity for specific carbohydrates; thus, they are also well placed for a potential role in mediating mammalian sperm–ZP binding. Indeed, a number of lectins and lectin-like proteins have been shown to be important for this binding, including rabbit sperm autoantigen,114 and the well-characterized ZP3R (formerly SP56). The ZP3R protein displays lectin-like affinity for galactose residues.115 Interestingly, galactose present at the non-reducing terminus of O-linked oligosaccharides, as well as ZP3R itself, has been demonstrated to have a role in sperm–zona binding in mouse.116, 117 Recent characterization of the ZP3R protein has also offered an interesting insight into the underlying capacitation-associated priming mechanisms required for sperm–ZP interactions. ZP3R was originally identified on the basis of photoaffinity crosslinking studies as a primary receptor for ZP3.115, 118 This role was subsequently discounted on the basis of ultrastructural evidence that revealed that the protein resided within the acrosomal matrix.119, 120 As such a location is incompatible with the mediation of primary ZP3 binding, it was postulated that the ZP3R was more likely to participate in secondary sperm–ZP interactions following the induction of acrosomal exocytosis. Resolution of these contradictory data was recently afforded by the demonstration that ZP3R, in addition to other acrosomal matrix proteins, is progressively released to the sperm surface during capacitation.121, 122 This dynamic change in localization suggests that part of the mechanism by which sperm attain their fully mature status involves the translocation of specific proteins from their initial acrosomal environment to regions of the plasma membrane capable of ZP interaction. Such a model challenges the widely held view of acrosomal exocytosis as an all or none reaction, and predicts that spermatozoa must have the potential to selectively traffic these proteins from the acrosome to the sperm surface. This would be both a unique and an intriguing mechanism that spermatozoa could employ to ensure that distinct receptor molecules are temporally presented to regulate their ability to bind the ZP.

Collectively, these data provide a strong argument against the traditional paradigm of sperm–ZP interaction being mediated by a solitary, constitutively expressed receptor. Indeed, on the basis of gene knockout studies, all of which have failed to induce the anticipated block to fertilization,113, 123, 124, 125 it is considered very unlikely that a single receptor could be solely responsible for supporting this important binding event. Interest has instead turned to models that feature molecular redundancy in which sperm–ZP binding is achieved through the concerted action of a number of zona receptor molecules. An alternative explanation for the large number of potential zona-binding candidates is that each species utilize their own unique repertoire of ZP receptors. This argument, however, appears to be at odds with the relatively high degree of cross-species conversation recorded among the known sperm–ZP receptors.112, 126, 127, 128, 129, 130 Nonetheless, recent data regarding the role of the sperm protein, zonadhesin, promises to improve our understanding of the mechanisms behind the species-specific nature of sperm–ZP binding.131 In this context, it has been shown that targeted deletion of zonadhesin leads to the production of mouse spermatozoa that bind promiscuously to the ZP of several divergent species.131

Formation of a multimeric zona recognition complex (MZRC)

Given the complexity of the post-testicular maturation events that precede acquisition of the ability to adhere to the ZP, it has recently been hypothesized that a cohort of sperm-based receptors may require active assembly and/or presentation in the form of a dynamic MZRC.132 This model of membrane priming draws interesting parallels with that of the early phases of membrane fusion that occur in many somatic cells.

Membrane priming

In a specialized cell, such as the spermatozoon, there are few intracellular domains, other than the acrosome, in which putative ZP receptors could be stored before surface presentation and assembly into an MZRC. The sperm acrosome is a sac-like vesicle that resides within the anterior aspect of the sperm head, positioned between the plasma membrane and the compact nucleus. This structure is enclosed within the inner acrosomal membrane and outer acrosomal membrane, which are located adjacent to the nucleus and sperm plasma membrane, respectively.133 In addition to the presence of numerous well-characterized hydrolytic enzymes (including hyaluronidase and acrosin) that participate in digestion of the ZP, the acrosome also contains a suite of glycoenzymes, the latter of which are a reflection of the fact that the organelle originates from the Golgi apparatus.

Interestingly, results of immunolocalization experiments on two such intra-acrosomal enzymes, β-d-galactosidase and β-d-glucuronidase, have highlighted that upon stimulation of capacitation in vitro, there is a time-dependent shift in their pattern of fluorescence.134 Specifically, their labeling changes from a thin, discrete lining to an intense spot-like pattern, the appearance of which may be because of contact between the outer acrosomal membrane and sperm plasma membrane, as capacitation progresses. This contact has been theorized to result from the binding of complementary SNARE proteins (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) and culminates in the production of fusion pores that provide a route for the presentation of the enzymes to the sperm surface.122 Such findings have since been extended to include a number of additional proteins such as arylsulfatase A,127, 128, 135 acrosin,136 hyaluronidase137 and ZP3R,119, 138 each of which show a capacitation-dependent relocalization from the acrosome to the sperm surface. The translocation of these proteins may thus prime spermatozoa for subsequent binding to the ZP.

Lipid rafts

As mentioned previously, lipid rafts have been implicated in establishment of ZP recognition by spermatozoa owing to their function as stable platforms in which proteins important in sperm–ZP binding can aggregate. Despite their stability,139 lipid rafts remain highly dynamic and have been observed to display considerable lateral movement in various cell types as a response to physiological stimuli or cellular activation events.140 In sperm, lipid rafts have been identified by the presence of several somatic cell raft markers including GM1 gangliosides, flotillin and proteins that have ‘raft' affinity owing to the presence of glycosylphosphatidylinositol anchors. A compelling functional link between lipid rafts, the construction of MZRCs and zona adhesion is supported by several lines of evidence. First, lipid rafts undergo an overt capacitation-associated reorganization from a uniform distribution to a pattern of confinement within the apical ridge of the sperm head,141, 142, 143 the precise region that mediates recognition and binding to the ZP. Second, clusters containing zona-binding molecules and lipid raft markers comigrate in the plasma membrane of live spermatozoa after cholesterol reduction.144 Finally, lipid raft markers and zona-binding molecules partition into low-density detergent-resistant phases of the sperm plasma membrane145 and accordingly, these fractions display affinity for the ZP.145, 146

Molecular chaperones

Though lipid rafts are proposed to function in the aggregation of specific receptor proteins, construction of a multimeric structure such as an MZRC would no doubt require more than just a simple aggregation of potential binding candidates. Consistent with this is evidence that a range of molecular chaperone proteins colocalize within lipid rafts.145 These molecular chaperones, or heat shock proteins (HSPs), have well-defined roles in the mediation of protein folding and trafficking, the assembly of multiprotein structures and the translocation of proteins across membranes.147, 148 HSPs have been found to be induced in cells prone to elevations in temperature, physical or chemical stress, viral infection, drugs and transforming agents, where they exhibit a protective role through maintenance of protein homeostasis and blockade of caspase-dependent apoptosis.149, 150 It should be noted, however, that whereas some members of the HSP family are only induced via stress, others are constitutively expressed and therefore are not susceptible to heat shock induction. The mammalian sperm surface has been demonstrated to express a number of HSP family members and a subset of these (HSP90B1, HSPA8 and HSPD1) has been detected within detergent resistant membranes.148, 151, 152 Not only do these HSPs localize to the same areas of the sperm plasma membrane as raft markers, but further evidence has indicated that HSP90B1 and HSPD1 also undergo capacitation-associated tyrosine phosphorylation, a modification necessary for their activation.153 These data support the model in which HSPs are involved in the conformational conversion and assembly of MZRCs at distinct locations on the sperm plasma membrane (that is, lipid rafts), and these regions correspond to those necessary for sperm–ZP interaction. Further work is, however, required to confirm the physical interaction between the HSPs and zona receptor proteins.

Conclusion

The three phases of sperm maturation, spermatogenesis, epididymal maturation and capacitation, greatly modify an inert, functionally incompetent cell into one that possesses fertilizing ability. Critical to the acquisition of this fertilizing ability is the substantial remodeling of the sperm plasma membrane that accompanies each of the stages. Capacitation-driven repositioning and selective aggregation of proteins believed to be important in sperm–ZP recognition are becoming increasingly well documented. It is also increasingly apparent that species-specific zona adhesion does not conform to a simple lock and key receptor–ligand interaction. On the contrary, the balance of evidence points toward models implicating multiple receptor molecules in sperm–ZP binding. The current suggestion is that aggregation of these receptor molecules at focal points on the sperm surface compatible with zona adhesion culminates in the assembly of an MZRC. Assembly of these MZRCs is believed to be effected through the action of molecular chaperones, which, together with their client proteins, are constricted to lipid rafts. The establishment of MZRCs may account for the elaborate level of modification necessary for production of functionally competent spermatozoa, and hence justify the enormous energy expenditure devoted to the sperm maturation process.

Notes

The authors declare no competing financial interests.

References

  • Chen JS, Doncel GF, Alvarez C, Acosta AA. Expression of mannose-binding sites on human spermatozoa and their role in sperm–zona pellucida binding. J Androl. 1995;16:55–63. [PubMed]
  • Chapman NR, Barratt CL. The role of carbohydrate in sperm–ZP3 adhesion. Mol Human Reprod. 1996;2:767–74. [PubMed]
  • Miranda PV, Gonzalez-Echeverria F, Marin-Briggiler CI, Brandelli A, Blaquier JA, et al. Glycosidic residues involved in human sperm–zona pellucida binding in vitro. Mol Human Reprod. 1997;3:399–404. [PubMed]
  • Gadella BM. The assembly of a zona pellucida binding protein complex in sperm. Reprod Domest Anim. 2008;43:12–9. [PubMed]
  • Population Division United Nations Department of Economic and Social Affairs; New YorkUSA; 2009. World population to exceed 9 billion by 2050.
  • Guttmacher Institute World Health Organization; GenevaSwitzerland; 2007. Facts on induced abortion worldwide.
  • Bhasin S. Approach to the infertile man. J Clin Endocrinol Metab. 2007;92:1995–2004. [PubMed]
  • Muratori M, Luconi M, Marchiani S, Forti G, Baldi E. Molecular markers of human sperm functions. Int J Androl. 2008;32:25–45. [PubMed]
  • Hermo L, Pelletier RM, Cyr DG, Smith CE. Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 1: background to spermatogenesis, spermatogonia, and spermatocytes. Microsc Res Tech. 2009;73:241–78. [PubMed]
  • Hermo L, Pelletier RM, Cyr DG, Smith CE. Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 2: changes in spermatid organelles associated with development of spermatozoa. Microsc Res Tech. 2009;73:279–319. [PubMed]
  • Hermo L, Pelletier RM, Cyr DG, Smith CE. Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 3: developmental changes in spermatid flagellum and cytoplasmic droplet and interaction of sperm with the zona pellucida and egg plasma membrane. Microsc Res Tech. 2009;73:320–63. [PubMed]
  • Hermo L, Pelletier RM, Cyr DG, Smith CE. Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage-gated channels, methylation/acetylation, and transcription factors. Microsc Res Tech. 2009;73:364–408. [PubMed]
  • Hermo L, Pelletier RM, Cyr DG, Smith CE. Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 5: intercellular junctions and contacts between germs cells and Sertoli cells and their regulatory interactions, testicular cholesterol, and genes/proteins associated with more than one germ cell generation. Microsc Res Tech. 2009;73:409–94. [PubMed]
  • Cornwall GA. New insights into epididymal biology and function. Hum Reprod Update. 2009;1:1–15. [PMC free article] [PubMed]
  • Bedford JM. Morphological changes in rabbit spermatozoa during passage through the epididymis. J Reprod Fertil. 1963;5:169–77. [PubMed]
  • Bedford JM. Changes in fine structure of the rabbit sperm head during passage through the epididymis. J Anat. 1965;99:891–906. [PubMed]
  • Horan AH, Bedford JM. Development of the fertilizing ability of spermatozoa in the epididymis of the Syrian hamster. J Reprod Fertil. 1972;30:417–23. [PubMed]
  • Saling PM. Development of the ability to bind to zonae pellucidae during epididymal maturation: reversible immobilization of mouse-spermatozoa by lanthanum. Biol Reprod. 1982;26:429–36. [PubMed]
  • Cuasnicu PS, Gonzalez Echeverria F, Piazza A, Blaquier JA. Addition of androgens to cultured hamster epididymis increases zona recognition by immature spermatozoa. J Reprod Fertil. 1984;70:541–7. [PubMed]
  • Fournier-Delpech S, Hamamah S, Tananis-Anthony C, Courot M, Orgebin-Crist M. Hormonal regulation of zona-binding ability and fertilizing ability of rat epididymal spermatozoa. Gamete Res. 1984;9:21–30.
  • Engel JC, Bernard EA, Wassermann GF. Protein synthesis by isolated spermatozoa from cauda and caput epididymis of rat. Acta Physiol Lat Am. 1973;23:358–62. [PubMed]
  • Cooper TG. Berlin: Springer-Verlag; 1986. The Epididymis, Sperm Maturation and Fertilisation.
  • Jones R, James PS, Howes L, Bruckbauer A, Klenerman D. Supramolecular organization of the sperm plasma membrane during maturation and capacitation. Asian J Androl. 2007;9:438–44. [PubMed]
  • Nikolopoulou M, Soucek DA, Vary JC. Changes in the lipid content of boar sperm plasma membranes during epididymal maturation. Biochim Biophys Acta. 1985;815:486–98. [PubMed]
  • Haidl G, Opper C. Changes in lipids and membrane anisotropy in human spermatozoa during epididymal maturation. Hum Reprod. 1997;12:2720–3. [PubMed]
  • Aitken RJ, Nixon B, Lin M, Koppers AJ, Lee YH, et al. Proteomic changes in mammalian spermatozoa during epididymal maturation. Asian J Androl. 2007;9:554–64. [PubMed]
  • Legare C, Berube B, Boue F, Lefievre L, Morales CR, et al. Hamster sperm antigen P26h is a phosphatidylinositol-anchored protein. Mol Reprod Dev. 1999;52:225–33. [PubMed]
  • Rejraji H, Sion B, Prensier G, Carreras M, Motta C, et al. Lipid remodeling of murine epididymosomes and spermatozoa during epididymal maturation. Biol Reprod. 2006;74:1104–13. [PubMed]
  • Frenette G, Girouard J, Sullivan R. Comparison between epididymosomes collected in the intraluminal compartment of the bovine caput and cauda epididymidis. Biol Reprod. 2006;75:885–90. [PubMed]
  • Asquith KL, Harman AJ, McLaughlin EA, Nixon B, Aitken RJ. Localization and significance of molecular chaperones, HSP1, and tumor rejection antigen gp96 in the male reproductive tract and during capacitation and acrosome reaction. Biol Reprod. 2005;72:328–37. [PubMed]
  • Griffiths GS, Galileo DS, Reese K, Martin-Deleon PA. Investigating the role of murine epididymosomes and uterosomes in GPI-linked protein transfer to sperm using SPAM1 as a model. Mol Reprod Dev. 2008;75:1627–36. [PubMed]
  • Yano R, Matsuyama T, Kaneko T, Kurio H, Murayama E, et al. Bactericidal/permeability-increasing protein is associated with the acrosome region of rodent epididymal spermatozoa. J Androl. 2010;31:201–14. [PubMed]
  • Austin CR. Observations on the penetration of the sperm in the mammalian egg. Aust J Sci Res B. 1951;4:581–96. [PubMed]
  • Chang MC. Fertilizing capacity of spermatozoa deposited into the fallopian tubes. Nature. 1951;168:697–8. [PubMed]
  • Austin CR. The ‘capacitation' of the mammalian sperm. Nature. 1952;170:326. [PubMed]
  • Aitken RJ, Harkiss D, Knox W, Paterson M, Irvine DS. A novel signal transduction cascade in capacitating human spermatozoa characterised by a redox-regulated, cAMP-mediated induction of tyrosine phosphorylation. J Cell Sci. 1998;111:645–56. [PubMed]
  • Baldi E, Luconi M, Bonaccorsi L, Muratori M, Forti G. Intracellular events and signaling pathways involved in sperm acquisition of fertilizing capacity and acrosome reaction. Front Biosci. 2000;5:E110–23. [PubMed]
  • Visconti PE, Bailey JL, Moore GD, Pan D, Olds-Clarke P, et al. Capacitation of mouse spermatozoa. I. Correlation between the capacitation state and protein tyrosine phosphorylation. Development. 1995;121:1129–37. [PubMed]
  • Nixon B, Aitken RJ, McLaughlin EA. New insights into the molecular mechanisms of sperm–egg interaction. Cell Mol Life Sci. 2007;64:1805–23. [PubMed]
  • Davis B. Timing of fertilization in mammals: sperm cholesterol/phospholipid ratio as a determinant of the capacitation interval. Proc Natl Acad Sci USA. 1981;78:7560–4. [PubMed]
  • Visconti PE, Ning X, Fornes MW, Alvarez JG, Stein P, et al. Cholesterol efflux-mediated signal transduction in mammalian sperm: cholesterol release signals an increase in protein tyrosine phosphorylation during mouse sperm capacitation. Dev Biol. 1999;214:429–43. [PubMed]
  • Langlais J, Kan FW, Granger L, Raymond L, Bleau G, et al. Identification of sterol acceptors that stimulate cholesterol efflux from human spermatozoa during in vitro capacitation. Gamete Res. 1988;20:185–201. [PubMed]
  • Davis B, Byrne R, Hungund B. Studies on the mechanism of capacitation II. Evidence for lipid transfer between plasma membrane of rat sperm and serum albumin during capacitation in vitro. Biochim Biophys Acta. 1979;558:257–66. [PubMed]
  • Martínez P, Morros A. Membrane lipid dynamics during human sperm capacitation. Front Biosci. 1996;1:d103–17. [PubMed]
  • Okamura N, Tajima Y, Soejima A, Masuda H, Sugita Y. Sodium bicarbonate in seminal plasma stimulates the motility of mammalian spermatozoa through direct activation of adenylate cyclase. J Biol Chem. 1985;260:9699–705. [PubMed]
  • Boatman DE, Robbins RS. Bicarbonate: carbon-dioxide regulation of sperm capacitation, hyperactivated motility, and acrosome reactions. Biol Reprod. 1991;44:806–13. [PubMed]
  • Garty NB, Salomon Y. Stimulation of partially purified adenylate cyclase from bull sperm by bicarbonate. FEBS Lett. 1987;218:148–52. [PubMed]
  • Chen Y, Cann MJ, Litvin TN, Iourgenko V, Sinclair ML, et al. Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. Science. 2000;289:625–8. [PubMed]
  • Gadella BM, Harrison RA. The capacitating agent bicarbonate induces protein kinase A-dependent changes in phospholipid transbilayer behavior in the sperm plasma membrane. Development. 2000;127:2407–20. [PubMed]
  • Gadella BM, Harrison RA. Capacitation induces cyclic adenosine 3′, 5′-monophosphate-dependent, but apoptosis-unrelated, exposure of aminophospholipids at the apical head plasma membrane of boar sperm cells. Biol Reprod. 2002;67:340–50. [PubMed]
  • Flesch FM, Brouwers JF, Nievelstein PF, Verkleij AJ, van Golde LM, et al. Bicarbonate stimulated phospholipid scrambling induces cholesterol redistribution and enables cholesterol depletion in the sperm plasma membrane. J Cell Sci. 2001;114:3543–55. [PubMed]
  • Harrison AP. Bicarbonate-induced membrane processing in sperm capacitation. Theriogenology. 2005;63:342–51. [PubMed]
  • Fraser LR. Mouse sperm capacitation in vitro involves loss of a surface-associated inhibitory component. J Reprod Fertil. 1984;72:373–84. [PubMed]
  • Ni Y, Zhou Y, Chen WY, Zheng M, Yu J, et al. HongrES1, a cauda epididymis-specific protein, is involved in capacitation of guinea pig sperm. Mol Reprod Dev. 2009;76:984–93. [PubMed]
  • Fraser LR. Interactions between a decapacitation factor and mouse spermatozoa appear to involve fucose residues and a GPI-anchored receptor. Mol Reprod Dev. 1998;51:193–202. [PubMed]
  • Gibbons R, Adeoya-Osiguwa SA, Fraser LR. A mouse sperm decapacitation factor receptor is phosphatidylethanolamine-binding protein 1. Reproduction. 2005;130:497–508. [PubMed]
  • Bi Y, Xu WM, Wong HY, Zhu H, Zhou ZM, et al. NYD-SP27, a novel intrinsic decapacitation factor in sperm. Asian J Androl. 2009;11:229–39. [PMC free article] [PubMed]
  • Pike LJ. Rafts defined: a report on the keystone symposium on lipid rafts and cell function. J Lipid Res. 2006;47:1597–8. [PubMed]
  • Simons K, Ikonen E. Functional rafts in cell membranes. Nature. 1997;387:569–72. [PubMed]
  • Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1:31–9. [PubMed]
  • Brown DA, London E. Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol. 1998;14:111–36. [PubMed]
  • Brown DA, London E. Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J Biol Chem. 2000;275:17221–4. [PubMed]
  • Schuck S, Honsho M, Ekroos K, Shevchenko A, Simons K. Resistance of cell membranes to different detergents. Proc Natl Acad Sci USA. 2003;100:5795–800. [PubMed]
  • Wassarman PM. Regulation of mammalian fertilization by zona pellucida glycoproteins. J Reprod Fertil Suppl. 1990;42:79–87. [PubMed]
  • Yanagimachi R. Fertility of mammalian spermatozoa: its development and relativity. Zygote. 1994;2:371–2. [PubMed]
  • Wassarman PM, Litscher ES. Mammalian fertilization: the egg's multifunctional zona pellucida. Int J Dev Biol. 2008;52:665–76. [PubMed]
  • Sinowatz F, Topfer-Petersen E, Kolle S, Palma G. Functional morphology of the zona pellucida. Anat Histol Embryol. 2001;30:257–63. [PubMed]
  • Bauskin AR, Franken DR, Eberspaecher U, Donner P. Characterization of human zona pellucida glycoproteins. Mol Human Reprod. 1999;5:534–40. [PubMed]
  • Lefievre L, Conner SJ, Salpekar A, Olufowobi O, Ashton P, et al. Four zona pellucida glycoproteins are expressed in the human. Hum Reprod. 2004;19:1580–6. [PubMed]
  • Goudet G, Mugnier S, Callebaut I, Monget P. Phylogenetic analysis and identification of pseudogenes reveal a progressive loss of zona pellucida genes during evolution of vertebrates. Biol Reprod. 2008;78:796–806. [PubMed]
  • Greve J, Wassarman P. Mouse egg extracellular coat is a matrix of interconnected filaments possessing a structural repeat. J Mol Biol. 1985;181:253–64. [PubMed]
  • Wassarman P, Mortillo S. Structure of the mouse egg extracellular coat, the zona pellucida. Int Rev Cytol. 1991. pp. 85–109. [PubMed]
  • Aitken R. The complexities of conception. Science. 1995;269:39–40. [PubMed]
  • Bleil JD, Wassarman PM. Mammalian sperm–egg interaction: identification of a glycoprotein in mouse egg zonae pellucidae possessing receptor activity for sperm. Cell. 1980;20:873–82. [PubMed]
  • Bleil J, Wassarman P. Structure and function of the zona pellucida: identification and characterization of the proteins of the mouse oocyte's zona pellucida. Dev Biol. 1980;76:185–202. [PubMed]
  • Vazquez M, Phillips D, Wassarman P. Interaction of mouse sperm with purified sperm receptors covalently linked to silica beads. J Cell Sci. 1989;92:713–22. [PubMed]
  • Florman H, Bechtol K, Wassarman P. Enzymatic dissection of the functions of the mouse egg's receptor for sperm. Dev Biol. 1984;106:243–55. [PubMed]
  • Mortillo S, Wassarman P. Differential binding of gold-labeled zona pellucida glycoproteins mZP2 and mZP3 to mouse sperm membrane compartments. Development. 1991;113:141. [PubMed]
  • Liu C, Litscher ES, Mortillo S, Sakai Y, Kinloch RA, et al. Targeted disruption of the mZP3 gene results in production of eggs lacking a zona pellucida and infertility in female mice. Proc Natl Acad Sci USA. 1996;93:5431–6. [PubMed]
  • Gwatkin R, Williams D. Receptor activity of the hamster and mouse solubilized zona pellucida before and after the zona reaction. Reproduction. 1977;49:55–9. [PubMed]
  • Hoodbhoy T, Dean J. Insights into the molecular basis of sperm–egg recognition in mammals. Reproduction. 2004;127:417–22. [PubMed]
  • Oikawa T, Nicolson G, Yanagimachi R. Inhibition of hamster fertilization by phytoagglutinins. Exp Cell Res. 1974;83:239–46. [PubMed]
  • Mori K, Daitoh T, Irahara M, Kamada M, Aono T. Significance of d-mannose as a sperm receptor site on the zona pellucida in human fertilization. Am J Obstet Gynecol. 1989;161:207–11. [PubMed]
  • Huang TT, Ohzu E, Yanagimachi R. Evidence suggesting that [ell]-fucose is part of a recognition signal for sperm–zona pellucida attachment in mammals. Gamete Res. 1982;5:355–61.
  • Shur BD, Hall NG. A role for mouse sperm surface galactosyltransferase in sperm binding to the egg zona pellucida. J Cell Biol. 1982;95:574–9. [PMC free article] [PubMed]
  • Shalgi R, Matityahu A, Nebel L. The role of carbohydrates in sperm–egg interaction in rats. Biol Reprod. 1986;34:446–52. [PubMed]
  • Oehninger S, Acosta A, Hodgen G. Antagonistic and agonistic properties of saccharide moieties in the hemizona assay. Fertil Steril. 1990;53:143. [PubMed]
  • Ahuja K, Gilburt D. Involvement of sperm sulphatases in early sperm–zona interactions in the hamster. J Cell Sci. 1985;78:247–61. [PubMed]
  • Oehninger S, Clark GF, Acosta AA, Hodgen GD. Nature of the inhibitory effect of complex saccharide moieties on the tight binding of human spermatozoa to the human zona pellucida. Fertil Steril. 1991;55:165–9. [PubMed]
  • Chen J, Litscher ES, Wassarman PM. Inactivation of the mouse sperm receptor, mZP3, by site-directed mutagenesis of individual serine residues located at the combining site for sperm. Proc Natl Acad Sci USA. 1998;95:6193–7. [PubMed]
  • Florman HM, Wassarman PM. O-linked oligosaccharides of mouse egg ZP3 account for its sperm receptor activity. Cell. 1985;41:313–24. [PubMed]
  • Litscher ES, Wassarman PM. Characterization of a mouse ZP3-derived glycopeptide, gp55, that exhibits sperm receptor and acrosome reaction-inducing activity in vitro. Biochemistry. 1996;35:3980–5. [PubMed]
  • Litscher ES, Juntunen K, Seppo A, Penttila L, Niemela R, et al. Oligosaccharide constructs with defined structures that inhibit binding of mouse sperm to unfertilized eggs in vitro. Biochemistry (Mosc) 1995;34:4662–9. [PubMed]
  • Rosiere T, Wassarman P. Identification of a region of mouse zona pellucida glycoprotein mZP3 that possesses sperm receptor activity. Dev Biol. 1992;154:309–17. [PubMed]
  • Easton RL, Patankar MS, Lattanzio FA, Leaven TH, Morris HR, et al. Structural analysis of murine zona pellucida glycans. J Biol Chem. 2000;275:7731–42. [PubMed]
  • Ellies LG, Tsuboi S, Petryniak B, Lowe JB, Fukuda M, et al. Core 2 oligosaccharide biosynthesis distinguishes between selectin ligands essential for leukocyte homing and inflammation. Immunity. 1998;9:881–90. [PubMed]
  • Stone EL, Ismail MN, Lee SH, Luu Y, Ramirez K, et al. Glycosyltransferase function in core 2-type protein O glycosylation. Mol Cell Biol. 2009;29:3770–82. [PMC free article] [PubMed]
  • Shi S, Williams SA, Seppo A, Kurniawan H, Chen W, et al. Inactivation of the Mgat1 gene in oocytes impairs oogenesis, but embryos lacking complex and hybrid N-glycans develop and implant. Mol Cell Biol. 2004;24:9920–9. [PMC free article] [PubMed]
  • Yonezawa N, Aoki H, Hatanaka Y, Nakano M. Involvement of N-linked carbohydrate chains of pig zona pellucida in sperm–egg binding. Eur J Biochem. 1995;233:35–41. [PubMed]
  • Nakano M, Yonezawa N, Hatanaka Y, Noguchi S. Structure and function of the N-linked carbohydrate chains of pig zona pellucida glycoproteins. J Reprod Fertil Suppl. 1996;50:25–34. [PubMed]
  • Chiu PC, Wong BS, Chung MK, Lam KK, Pang RT, et al. Effects of native human zona pellucida glycoproteins 3 and 4 on acrosome reaction and zona pellucida binding of human spermatozoa. Biol Reprod. 2008;79:869–77. [PubMed]
  • Chapman N, Kessopoulou E, Andrews P, Hornby D, Barratt CR. The polypeptide backbone of recombinant human zona pellucida glycoprotein-3 initiates acrosomal exocytosis in human spermatozoa in vitro. Biochem J. 1998;330 Pt 2:839–45. [PubMed]
  • Hinsch E, Aires VA, Hedrich F, Oehninger S, Hinsch KD. A synthetic decapeptide from a conserved ZP3 protein domain induces the G protein-regulated acrosome reaction in bovine spermatozoa. Theriogenology. 2005;63:1682–94. [PubMed]
  • Dean J. Reassessing the molecular biology of sperm–egg recognition with mouse genetics. Bioessays. 2004;26:29–38. [PubMed]
  • Dean J. Molecular biology of sperm–egg interactions. Andrologia. 2005;37:198–9. [PubMed]
  • Rodeheffer C, Shur BD. Characterization of a novel ZP3-independent sperm-binding ligand that facilitates sperm adhesion to the egg coat. Development. 2004;131:503–12. [PubMed]
  • Lyng R, Shur BD. Mouse oviduct-specific glycoprotein is an egg-associated ZP3-independent sperm-adhesion ligand. J Cell Sci. 2009;122:3894–906. [PubMed]
  • Miller DJ, Macek MB, Shur BD. Complementarity between sperm surface beta-1,4-galactosyltransferase and egg-coat ZP3 mediates sperm–egg binding. Nature. 1992;357:589–93. [PubMed]
  • Shur BD, Neely CA. Plasma membrane association, purification, and partial characterization of mouse sperm beta 1,4-galactosyltransferase. J Biol Chem. 1988;263:17706–14. [PubMed]
  • Gong X, Dubois DH, Miller DJ, Shur BD. Activation of a G protein complex by aggregation of beta-1,4-galactosyltransferase on the surface of sperm. Science. 1995;269:1718–21. [PubMed]
  • Chiu PC, Chung MK, Koistinen R, Koistinen H, Seppala M, et al. Glycodelin-A interacts with fucosyltransferase on human sperm plasma membrane to inhibit spermatozoa–zona pellucida binding. J Cell Sci. 2007;120:33–44. [PubMed]
  • Cornwall G, Tulsiani D, Orgebin-Crist M. Inhibition of the mouse sperm surface alpha-d-mannosidase inhibits sperm–egg binding in vitro. Biol Reprod. 1991;44:913–21. [PubMed]
  • Lu Q, Shur BD. Sperm from beta 1,4-galactosyltransferase-null mice are refractory to ZP3-induced acrosome reactions and penetrate the zona pellucida poorly. Development. 1997;124:4121–31. [PubMed]
  • O'Rand MG, Widgren EE, Fisher SJ. Characterization of the rabbit sperm membrane autoantigen, RSA, as a lectin-like zona binding protein. Dev Biol. 1988;129:231–40. [PubMed]
  • Bleil JD, Wassarman PM. Identification of a ZP3-binding protein on acrosome-intact mouse sperm by photoaffinity crosslinking. Proc Natl Acad Sci USA. 1990;87:5563–7. [PubMed]
  • Bleil J, Wassarman P. Galactose at the nonreducing terminus of O-linked oligosaccharides of mouse egg zona pellucida glycoprotein ZP3 is essential for the glycoprotein's sperm receptor activity. Proc Natl Acad Sci USA. 1988;85:6778–82. [PubMed]
  • Buffone MG, Zhuang T, Ord TS, Hui L, Moss SB, et al. Recombinant mouse sperm ZP3-binding protein (ZP3R/sp56) forms a high order oligomer that binds eggs and inhibits mouse fertilization in vitro. J Biol Chem. 2008;283:12438–45. [PubMed]
  • Cheng A, Le T, Palacios M, Bookbinder LH, Wassarman PM, et al. Sperm–egg recognition in the mouse: characterization of sp56, a sperm protein having specific affinity for ZP3. J Cell Biol. 1994;125:867–78. [PMC free article] [PubMed]
  • Kim KS, Cha MC, Gerton GL. Mouse sperm protein sp56 is a component of the acrosomal matrix. Biol Reprod. 2001;64:36–43. [PubMed]
  • Foster JA, Friday BB, Maulit MT, Blobel C, Winfrey VP, et al. AM67, a secretory component of the guinea pig sperm acrosomal matrix, is related to mouse sperm protein sp56 and the complement component 4-binding proteins. J Biol Chem. 1997;272:12714–22. [PubMed]
  • Kim KS, Gerton GL. Differential release of soluble and matrix components: evidence for intermediate states of secretion during spontaneous acrosomal exocytosis in mouse sperm. Dev Biol. 2003;264:141–52. [PubMed]
  • Tulsiani DRP, Abou-Haila A. Is sperm capacitation analogous to early phases of Ca2+-triggered membrane fusion in somatic cells and viruses. Bioessays. 2004;26:281–90. [PubMed]
  • Inoue N, Ikawa M, Nakanishi T, Matsumoto M, Nomura M, et al. Disruption of mouse CD46 causes an accelerated spontaneous acrosome reaction in sperm. Mol Cell Biol. 2003;23:2614–22. [PMC free article] [PubMed]
  • Cho C, O'Dell Bunch D, Faure JE, Goulding EH, Eddy EM, et al. Fertilization defects in sperm from mice lacking fertilin beta. Science. 1998;281:1857–9. [PubMed]
  • Ensslin MA, Shur BD. Identification of mouse sperm SED1, a bimotif EGF repeat and discoidin-domain protein involved in sperm–egg binding. Cell. 2003;114:405–17. [PubMed]
  • Rattanachaiyanont M, Weerachatyanukul W, Leveille MC, Taylor T, D'Amours D, et al. Anti-SLIP1-reactive proteins exist on human spermatozoa and are involved in zona pellucida binding. Mol Hum Reprod. 2001;7:633–40. [PubMed]
  • Carmona E, Weerachatyanukul W, Soboloff T, Fluharty A, White D, et al. Arylsulfatase A is present on the pig sperm surface and is involved in sperm–zona pellucida binding. Dev Biol. 2002;247:182–96. [PubMed]
  • Tantibhedhyangkul J, Weerachatyanukul W, Carmona E, Xu H, Anupriwan A, et al. Role of sperm surface arylsulfatase A in mouse sperm–zona pellucida binding. Biol Reprod. 2002;67:212. [PubMed]
  • Tulsiani D, Skudlarek M, Orgebin-Crist M. Novel alpha-d-mannosidase of rat sperm plasma membranes: characterization and potential role in sperm–egg interactions. J Cell Biol. 1989;109:1257–67. [PMC free article] [PubMed]
  • Tulsiani D, Skudlarek M, Orgebin-Crist M. Human sperm plasma membranes possess alpha-d-mannosidase activity but no galactosyltransferase activity. Biol Reprod. 1990;42:843–58. [PubMed]
  • Tardif S, Wilson MD, Wagner R, Hunt P, Gertsenstein M, et al. Zonadhesin is essential for species specificity of sperm adhesion to the egg's zona pellucida. J Biol Chem. 2010;285:24863–70. [PubMed]
  • Nixon B, Asquith KL, John Aitken R. The role of molecular chaperones in mouse sperm–egg interactions. Mol Cell Endocrinol. 2005;240:1–10. [PubMed]
  • Abou-Haila A, Tulsiani DR. Mammalian sperm acrosome: formation, contents, and function. Arch Biochem Biophys. 2000;379:173–82. [PubMed]
  • Abou-Haila A, Tulsiani DR. Evidence for the capacitation-associated membrane priming of mouse spermatozoa. Histochem Cell Biol. 2003;119:179–87. [PubMed]
  • Yang CH, Srivastava PN, Williams WL. Purification and properties of aryl sulfatases from rabbit sperm acrosomes. Proc Soc Exp Biol Med. 1974;145:721–5. [PubMed]
  • Tesarik J, Drahorad J, Testart J, Mendoza C. Acrosin activation follows its surface exposure and precedes membrane fusion in human sperm acrosome reaction. Development. 1990;110:391–400. [PubMed]
  • Meyers SA, Rosenberger AE. A plasma membrane-associated hyaluronidase is localized to the posterior acrosomal region of stallion sperm and is associated with spermatozoal function. Biol Reprod. 1999;61:444–51. [PubMed]
  • Kim KS, Foster JA, Gerton GL. Differential release of guinea pig sperm acrosomal components during exocytosis. Biol Reprod. 2001;64:148–56. [PubMed]
  • Nixon B, Aitken RJ. The biological significance of detergent-resistant membranes in spermatozoa. J Reprod Immunol. 2009;83:8–13. [PubMed]
  • Simons K, Vaz WLC. Model systems, lipid rafts, and cell membranes. Annu Rev Biophys Biomol Struct. 2004;33:269–95. [PubMed]
  • Shadan S, James PS, Howes EA, Jones R. Cholesterol efflux alters lipid raft stability and distribution during capacitation of boar spermatozoa. Biol Reprod. 2004;71:253–65. [PubMed]
  • Gibbs GM, Lo JC, Nixon B, Jamsai D, O'Connor AE, et al. Glioma pathogenesis-related 1-like 1 is testis enriched, dynamically modified, and redistributed during male germ cell maturation and has a potential role in sperm–oocyte binding. Endocrinology. 2010;151:2331–42. [PubMed]
  • van Gestel RA, Brewis IA, Ashton PR, Helms JB, Brouwers JF, et al. Capacitation-dependent concentration of lipid rafts in the apical ridge head area of porcine sperm cells. Mol Hum Reprod. 2005;11:583–90. [PubMed]
  • Jones R, Howes E, Dunne PD, James P, Bruckbauer A, et al. Tracking diffusion of GM1 gangliosides and zona pellucida binding molecules in sperm plasma membranes following cholesterol efflux. Dev Biol. 2010;339:398–406. [PubMed]
  • Nixon B, Bielanowicz A, McLaughlin EA, Tanphaichitr N, Ensslin MA, et al. Composition and significance of detergent resistant membranes in mouse spermatozoa. J Cell Physiol. 2009;218:122–34. [PubMed]
  • Khalil MB, Chakrabandhu K, Xu H, Weerachatyanukul W, Buhr M, et al. Sperm capacitation induces an increase in lipid rafts having zona pellucida binding ability and containing sulfogalactosylglycerolipid. Dev Biol. 2006;290:220–35. [PubMed]
  • Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell. 2006;125:443–51. [PubMed]
  • Naaby-Hansen S, Herr JC. Heat shock proteins on the human sperm surface. J Reprod Immunol. 2010;84:32–40. [PMC free article] [PubMed]
  • Santoro MG, Amici C, Rossi A. Role of heat shock proteins in viral infectionIn: Pockley AG, Calderwood SK, Santoro MG, editors. Prokaryotic and Eukaryotic Heat Shock Proteins in Infectious Disease Dordrecht: Springer; 2010. 51–84.84.
  • Joly AL, Wettstein G, Mignot G, Ghiringhelli F, Garrido C. Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J Innate Immun. 2010;2:238–47. [PubMed]
  • Miller D, Brough S, Al-Harbi O. Characterization and cellular distribution of human spermatozoal heat shock proteins. Hum Reprod. 1992;7:637–45. [PubMed]
  • Walsh A, Whelan D, Bielanowicz A, Skinner B, Aitken RJ, et al. Identification of the molecular chaperone, heat shock protein 1 (chaperonin 10), in the reproductive tract and in capacitating spermatozoa in the male mouse. Biol Reprod. 2008;78:983–93. [PubMed]
  • Asquith KL, Baleato RM, McLaughlin EA, Nixon B, Aitken RJ. Tyrosine phosphorylation activates surface chaperones facilitating sperm-zona recognition. J Cell Sci. 2004;117:3645–57. [PubMed]
  • Fraser LR, Harrison RAP, Herod JE. Characterization of a decapacitation factor associated with epididymal mouse spermatozoa. Reproduction. 1990;89:135–48. [PubMed]
  • Adeoya-Osiguwa SA, Fraser LR. Evidence for Ca2+-dependent ATPase activity, stimulated by decapacitation factor and calmodulin, in mouse sperm. Mol Reprod Dev. 1996;44:111–20. [PubMed]
  • Visconti PE, Galantino-Homer H, Ning X, Moore GD, Valenzuela JP, et al. Cholesterol efflux-mediated signal transduction in mammalian sperm. Beta-cyclodextrins initiate transmembrane signaling leading to an increase in protein tyrosine phosphorylation and capacitation. J Biol Chem. 1999;274:3235–42. [PubMed]
  • de Vries KJ, Wiedmer T, Sims PJ, Gadella BM. Caspase-independent exposure of aminophospholipids and tyrosine phosphorylation in bicarbonate responsive human sperm cells. Biol Reprod. 2003;68:2122–34. [PubMed]
  • Visconti PE. Understanding the molecular basis of sperm capacitation through kinase design. Proc Natl Acad Sci USA. 2009;106:667–8. [PubMed]
  • Visconti PE, Moore GD, Bailey JL, Leclerc P, Connors SA, et al. Capacitation of mouse spermatozoa. II. Protein tyrosine phosphorylation and capacitation are regulated by a cAMP-dependent pathway. Development. 1995;121:1139–50. [PubMed]
  • Nixon B, Bielanowicz A, Anderson AL, Walsh A, Hall T, et al. Elucidation of the signaling pathways that underpin capacitation-associated surface phosphotyrosine expression in mouse spermatozoa. J Cell Physiol. 2010;224:71–83. [PubMed]
  • Baibakov B, Gauthier L, Talbot P, Rankin TL, Dean J. Sperm binding to the zona pellucida is not sufficient to induce acrosome exocytosis. Development. 2007;134:933. [PubMed]
  • Mayorga LS, Tomes CN, Belmonte SA. Acrosomal exocytosis, a special type of regulated secretion. IUBMB life. 2007;59:286–92. [PubMed]

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