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Oocyte–sperm interactions
Animal Reproduction Science 60–61 Ž2000. 653–662 www.elsevier.comrlocateranireprosci
Oocyte–sperm interactions ) Edda Topfer-Petersen , Anna M. Petrounkina, ¨ Mahnaz Ekhlasi-Hundrieser Institute of ReproductiÕe Medicine, School of Veterinary Medicine, Bunteweg 15, ¨ D-30559 HannoÕer, Germany
Abstract The penetration of the zona pellucida is a crucial step during fertilization. Spermatozoa that are unable to recognize and bind to the zona pellucida glycoproteins or respond to the zona pellucida by undergoing the acrosome reaction fail to fertilize the egg. In most mammalian species, after entering the fallopian tube sperm are stored in the isthmic part of the oviduct under conditions that maintain sperm viability and synchronize both sperm transport and the process of acquisition of fertilizing ability, called capacitation. Only capacitated sperm are enabled to recognize the oocyte and respond to the oocyte signals in an appropriate manner. Close to time of ovulation sperm are released from the oviductal epithelium and swim to site of fertilization. The oviduct and the oocyte itself appear to coordinate sperm function and gamete interaction. The gamete recognition and the next levels of interaction are probably granted by the carbohydrate–protein interactions. Upon binding the signal cascade leading to acrosomal exocytosis is activated, eventually initiated by aggregation of zona pellucida receptor molecules. These signal transducing mechanisms are primed during the capacitation process. Tyrosine phosphorylation, tightly connected to the cholesterol efflux from the plasma membrane, and hyperpolarization seem be involved in this priming by activation of Ca2q pathways. Further preparational steps of the acrosome reaction may be mediated by osmosensitive signal transducing mechanisms. The current perspective focuses on the molecules involved in the complex hierarchy of sperm–egg interactions and regulative events priming sperm cell during capacitation for the acrosome reaction. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Sperm; Egg; Gamete recognition; Carbohydrate–protein interaction; Capacitation; Acrosome reaction
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Corresponding author. Tel.: q49-511-9538520; fax: q49-51-9538504. .. E-mail address: [email protected] ŽE. Topfer-Petersen ¨
0378-4320r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0 3 7 8 - 4 3 2 0 Ž 0 0 . 0 0 1 2 8 - 7
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1. Introduction The penetration of the oocyte zona pellucida is a crucial step during fertilization. The zona pellucida is the extracellular network-like matrix enveloping the egg that protects the growing egg and the preimplantation embryo against physical damages. Sperm that are unable to recognize and bind to the zona pellucida glycoproteins, as well as sperm, upon binding, that are unable to respond with it by undergoing the acrosome reaction fail to fertilize the egg. After entering the Fallopian tube sperm are stored in the isthmic part of the oviduct by binding to the ciliated cell lining the oviductal epithelium ŽSuarez, 1999.. Sperm are stored under conditions that maintain sperm viability and synchronize sperm transport and the capacitating process. This enables sperm to interact with the oocyte in the appropriate manner. Reaching the site of fertilization sperm recognize the egg by carbohydrate–protein interactions. It is well accepted that the corresponding carbohydrate-binding proteins of the sperm surface bind defined oligosaccharide ligands of the zona pellucida. Upon binding the signaling cascade leading to the acrosomal exocytosis Žacrosome reaction. is activated. This allows sperm to penetrate the zona pellucida. After penetrating the zona pellucida sperm interact and fuse with egg vitelline membrane and trigger thus the embryonic development program ŽYanagimachi, 1994.. The current perspective focuses on the molecules involved in the complex hierarchy of interactions between sperm and egg in pig and other domestic animals.
2. Molecules involved in gamete recognition Close to the time of ovulation sperm are released from the oviductal epithelium and swim to the site of fertilization to meet the egg. The hyperactivated motility that sperm develop during the capacitating process not only enables the sperm to reach the oocyte but also may be necessary for the collision with the egg assisting the manifestation of the adhesion between sperm and egg ŽThaler and Cardullo, 1996.. The adhesion between both gametes is a complex sequence of binding events implicating low and high affinity binding sites ŽThaler and Cardullo, 1996.. The fundamental mechanism of gamete recognition appears to be conserved throughout the evolution from marine invertebrates to eutherian mammals and is based on carbohydrate–protein interactions between the sperm and the oocyte envelope. Oligosaccharides that are presented with a certain arrangement within the supramolecular architecture of the egg envelope are recognized by complementary carbohydrate receptors of the sperm, thereby mediating gamete recognition and coordinating sperm functions to warrant fertilization.
3. Zona pellucida The mammalian zona pellucida is composed of three glycoproteins that are products of the three zona pellucida genes named according to their length: ZPA, ZPB and ZPC
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genes ŽHarris et al., 1994.. In rodents zp glycoproteins are exclusively synthesized by the oocyte whereas, in domestic animals possessing a thick zona pellucida, e.g. in pig and cow, during follicular development the surrounding follicle cells contribute to the formation of the extra cellular matrix Žfor review see Sinowatz et al., 1999.. The three proteins build a typical fibrogranular structure by noncovalent interactions presenting a complex and highly heterogeneous mixture of asparagine ŽN.- and serinerthreonine ŽO.-linked oligosaccharide side chains. It has been proved that in different mammalian species amino acid sequence of the zp glycoproteins is highly conserved between different mammalian species. However, variable posttranslational glycosylation and processing of the polypeptide chains as well as the variable assembling of the supramolecular structure of the zp matrix Žpossibly due to differing biosynthetic pathways. lead to substantial differences of zp structure and function between rodents Žmouse. and domestic animals Žpig.. In mouse the zona pellucida protein 3 ŽmZP3 encoded by the ZPC gene. carrying the sperm receptor activity and the acrosome reaction-inducing potency forms together with zona pellucida protein 2 ŽmZP2 encoded by the ZPA gene. long periodically heterodimeric filaments that are randomly interconnected with the zona pellucida protein 1 ŽmZP1 encoded by the ZPB gene. ŽWassarman and Mortillo, 1991.. In contrast, in pig the biological active zp protein has been found to be ZPB Žthe mZP1 homologue. that tends to aggregate with ZPC Žthe mZP3 homologue. thereby increasing the sperm binding capacity ŽYurewicz et al., 1998.. Murine zp proteins can be separated by SDS-PAGE showing molecular masses of 80 kDa ŽZP3rZPC., 120 kDa ŽZP2rZPA. and 220 kDa ŽZP1ŽZPB. Žreviewed by Wassarman, 1999.. In pig the zona pellucida protein 3 ŽpZP3. has been shown to be a mixture of the so-called pZP3a ŽZPB. and pZP3b ŽZPB. with apparent molecular masses of 55 kDa and in cow the ZP3arb homologues reveal overlapping bands Ž78–88 kDa. after 2-D PAGE ŽNoguchi and Nakano, 1992; Topper et al., 1997.. Information on the oligosaccharide structure of zp glycoproteins is almost complete for pig and partially available for mouse and cow ŽHokke et al., 1994; Nakano et al., 1996; Topfer-Petersen, 1999.. Although the ¨ structures of the oligosaccharide chains are basically the same in these three species, they differ in the percentage and structure of the neutral N-linked carbohydrates. Whereas, in mouse the N-glycans are almost acidic, the major neutral N-glycans Žabout 25%. of the porcine zp glycoproteins belong to the bi-antennary fucosylated complex N-type and is a high mannose-type in cattle. In cattle the major neutral N-glycan has been implicated in sperm–egg recognition ŽNakano et al., 1996. and may bind to still poorly described mannose-binding proteins of the capacitated sperm ŽSuarez, personal communication.. In pig sperm receptor activity has been mapped to O- and N-linked glycans of ZPB ŽYurewicz et al., 1991; Yonezawa et al., 1995.. The trirtetra-antennary N-glycans localized in the N-terminal region of the mature ZPB ŽpZP3a . mediate the binding of sperm to the zona pellucida whereas, the structural identical trirtetra-antennary N-glycans of the ZPC molecule ŽpZP3b . appear to play no role in gamete recognition ŽKudo et al., 1998, Yonezawa et al., 1999.. The only difference between these oligosaccharides is the C-terminally localized glycosylation site within the ZPC molecule, possibly leading to a reduced accessibility of the glycan chains, dependent on folding of the protein ŽFig. 1.. This observation emphasizes that the assembling of the zp glycoproteins and the correct presentation of the biological active oligosaccharides
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Fig. 1. Schematic presentation of the known N-glycosylation sites in porcine zp glycoproteins. Of the six potential N-glycosylation sites of ZPA only Asn268 has been identified carrying biantennary N-glycans ŽTopfer-Petersen, unpublished.. ZPB and ZPC both possess three glycosylation sites ŽKudo et al., 1998; ¨ Yonezawa et al., 1999.. The mature ZPB molecule is N-terminally processed ŽAsp 137. and the mature ZPC molecule losses the signal peptide and is N-terminally blocked Žpyro-Gln23.. Signal peptide is marked in grey.
within the three-dimensional structure are important features to achieve the physiological relevant binding between both gametes. In mouse low- and high-affinity binding sites have been identified on the sperm surface implicating a hierarchy of binding events ŽJohnston et al., 1998.. Interestingly, the high-affinity site recognizing fucosylated oligosaccharides can be occupied with less affinity by other carbohydrate structures. The multivalent presentation of the biological active oligosaccharides may be a necessity to create high-affinity binding. In mouse the relevant O-linked oligosaccharides are clustered at the C-terminal sperm-combing sites of mZPC Žreviewed by Wassarman, 1999.. In pig the arrangement of the oligosaccharides within the heteromultimeric ZPBrZPC complex may be responsible for the manifestation of high-affinity binding to the sperm ŽYurewicz et al., 1998.. There is a considerable controversy regarding the structural entity of the sperm oligosaccharide ligands in both species suggesting that Ži. different experimental conditions Žand the possible binding of uncapacitated and capacitated sperm to the zona; Miranda, 1998. andror Žii. an allowed structural variety of the presented carbohydrates at the sperm-binding site of the intact zona pellucida may account for these differences.
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4. Zona pellucida binding proteins A long list of putative zona pellucida receptors has been described up to date. However, only few are characterized regarding their carbohydrate specificity and structure of the carbohydrate-binding domain, e.g. rabbit sp17, mouse galactosyltransferase, porcine spermadhesins and proracrosin. Spermadhesins represent a new class of lectins with specificity to galactose-containing structures, mannose or mannose-6-phosphate, whereas, proacrosin binds to zp glycoproteins following a sulfate-recognition mechanism. Similarly, sp17 recognizes sulfated carbohydrate as they are presented in the zona pellucida and fucoidan and share consensus sequences with the class of C-type lectins. Porcine zonadhesin and mouse sp56 are proteins containing a molecular structure with still unknown ligand-binding specificity. Zona receptor kinases Žmouse p95 and human hu9. ZRK and human fertility antigen A-1 ŽFA-1. are autophosphorylated in response to the zona pellucida exhibiting an intrinsic signaling potential. Some proteins have been found by targeted mutagenesis not to be particularly relevant to gamete recognition Že.g. mouse galactosyltransferase.. They may rather function in earlier events such as capacitating and sperm–oviduct interactions Žspermadhesins.. Others are obviously located in the wrong compartment of the sperm to participate in gamete recognition or primary binding Že.g. proracrosin and PH-20.. These may rather be involved in the transient secondary binding of acrosome-reacted sperm during zona penetration Žreviewed by Naz Rajesh, 1996; McLesky et al., 1998; Shur, 1998; Topfer¨ Petersen, 1999..
5. Receptor aggregation initiates acrosome reaction The first evidence that the aggregation of zona pellucida receptor molecules within the plane of the sperm membrane triggers the signaling cascade resulting in acrosome reaction was demonstrated by Leyton and Saling Ž1989.. Zp glycoproteins and antibodies directed against zona receptor kinase ŽZRK., galactosyltransferase and some other sperm surface proteins are able to initiate the acrosome reaction whereas, a zp glycopeptide fraction retaining sperm binding ability and univalent Fab-fragments fail to induce the acrosome reaction ŽMcLesky et al., 1998; Shur, 1998.. Putative zona pellucida binding proteins have been found to traverse the sperm plasma membrane as ZRK, galactosyltransferase, human FA-1 and porcine zonadhesin whereas, porcine p47, spermadhesins and murine proteinase inhibitor-binding protein are peripherally associated to the sperm surface ŽAarons et al., 1991; Naz Rajesh, 1996; McLesky et al., 1998; Shur, 1998; Topfer-Petersen, 1999.. Those surface-associated and transmembrane pro¨ teins may form the multimeric receptor upon binding to the zona pellucida thus initiating the aggregation of the signaling molecules of the receptor complex ŽZRK, galactosyltransferase, zonadhesin or other still unknown components. that then trigger the different pathways of acrosome reaction ŽFlorman et al., 1998.. The postulated multimeric sperm receptor ŽShur, 1998. may be composed by a varying set of proteins without loosing completely the ability to initiate recognition and to trigger the acrosome.
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The following model of the ionic events in ZP signal transduction is largely based on the information reviewed by Florman et al. Ž1998.. According to this model the activation of the sperm surface receptor by the association with mouse ZP3 initiates two separate pathways. One signaling sequence leads to the activation of a cation channel C producing inward currents depolarizing sperm membrane potential and opening low voltage-activated T-type Ca2q channel. The other pathway initiates internal alkalinization by mechanisms likely reflecting the mediation of G proteins. This pH increase and transient Ca2q current in response to ZP or membrane depolarization promote a sustained Ca2q increase. The elevation of Ca2q level, a rise of intracellular pH and the enhancement of membrane fusogenity are postulated to be the driving forces triggering the cascade of acrosomal expcytosis ŽHarrison and Roldan, 1990; Roldan and Harrison, 1990; Kopf and Gerton, 1991; Aitken, 1997..
6. Priming of signal transducing mechanisms during capacitation Ejaculated mammalian sperm need a period of incubation in the female reproductive tract in order to acquire the capacity to fertilize an egg ŽYanagimachi, 1994.. This period of attaining functional competence, referred to as capacitation ŽAustin, 1951., is required for undergoing the acrosome reaction induced by physiological stimuli such as ZP ŽFlorman and First, 1988.. Since the response to the oocyte signals can be initiated only in capacitated sperm, the signal-transducing mechanisms appear to be primed during capacitation. Capacitation is accompanied by an increase of membrane fluidity and remodeling of the sperm surface, protein phosphorylation, an increase of internal Ca2q and pH and membrane hyperpolarization ŽStorey, 1995.. Generally accepted is the concept of capacitation as series of positive destabilizing events ŽHarrison, 1996.. The initial event is the BSArLDH-mediated cholesterol efflux resulting in an increase of plasma membrane fluidity thus supporting membrane remodeling ŽDavis et al., 1979; Visconti et al., 1999.. Kinase-mediated tyrosine posphorylations are tightly connected with this event ŽVisconti et al., 1994a,b.. Tyrosine phosphorylation appears to be an essential process of capacitation: if tyrosine kinase inhibitors block it the spermatozoa lose the ability to respond to physiological agonists ŽAitken et al., 1996.. Since cross talk with cAMP is involved in the regulation of protein tyrosine phosphorylation, it is tempting to speculate that the loss of cholesterol may be involved in the regulation of cAMP pathway. The monotonic elevating of Ca2q with the rate about 0.5 nmrmin seems to be insufficient to initiate acrosome reaction and might occur due to the modulation of Ca2q-ATPase activity. The mechanism related to voltage-dependent T-channel described above ŽFlorman et al., 1998 and references therein. appears to be responsible for the explosive increase of Ca2q in response to physiological agonists leading to the acrosomal exocytosis. The sperm T-channel may be primed and held in steady state during capacitating by hyperpolarization Žprobably due to Kq-permeability contribution. at the level of an upstream action channel and by tyrosine phosphorylation. The tyrosine phosphorylation of T-channel or channel regulator decreases Ca2q current through the channel prevent-
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ing the acrosome reaction, whereas, the dephosphorylation may stimulate the activation of the channel ŽArnoult et al., 1997.. However, it appears that further signal transduction mechanisms may be involved in the activation of Ca2q pathways. A mild hypoosmotic shock has been shown to be a potent stimulus of the acrosome reaction. Rossato et al. Ž1996. demonstrated that human spermatozoa possess Ca2q influx pathways activated by plasma membrane stretching. A blocker of mechano-sensitive Ca2q channels ŽGdq. diminished osmotically sensitive Ca2q-rises in a dose-dependent manner and completely blocked the osmotically sensitive acrosome reaction. The formal evidence is missing that Ca2q rise occurs via Ca2q channels, but this hypothesis seems likely due to fast kinetics, sensitivity to membrane depolarization and Gdq treatment. Osmosensitive mechanisms may also play a role during preparation steps of the acrosome reaction Žcapacitation.. The regulation mediated by osmotic events may be reflected in cell volume behavior during capacitation. Boar sperm cell volume tends to show cyclical variations during incubation under capacitating conditions with the frequency varying dependent on the incubation conditions. The expression of different levels of swelling at fixed osmotic conditions is coupled to the change in cell osmole content. The osmosensing regulatory performance, such as swelling and subsequent regulatory volume decrease, could be modulated during capacitation and may reflect the ongoing destabilization of the membrane on earlier stages of capacitation treatment ŽPetrounkina et al., 2000.. Preliminary studies on boar sperm let suggest that Ži. changes in cell volume are closely related to the expression of tyrosine phosphorylation as shown by indirect immunfluorescence on the earlier stages of incubation under capacitation conditions, and Žii. cell volume regulation is mediated in the first line by quinine-sensitive channels ŽPetrounkina et al., 2000.. The participation of quinine-sensitive channels on cell volume regulation of bull sperm was reported by Kulkarni et al. Ž1997.. For other cell types Že.g. in erythrocytes. protein tyrosine phosphorylation has already been found to be osmo- and volume-sensitive ŽMush et al., 1994, 1998.. Hypoosmotic shock triggered a rapid increase in tyrosine phosphorylation; furthermore, the volume regulation of swollen cells was sensitive to tyrosine phosphatase inhibition. Phosphorylation of a band 3 protein in human erythrocytes, observed by ionophore treatment or shrinkinginduced volume regulation, was suppressed by quinine, an inhibitor of Ca2q-activated Kq channel ŽMinetti et al., 1996.. Moving into field of speculation, the similar modulation of osmosensing signal transduction by tyrosine phosphorylation may be expected also in sperm cells while priming for activation in response to ZP and for zona penetration. Further studies are in progress to investigate this hypothetical regulatory mechanism of signal transduction during capacitation.
7. Conclusion During the capacitating process several of regulative events including osmo-sensitive mechanisms appear to prime the sperm cell awaiting the oocyte signals to enter an
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activated stage and be able to fertilize the egg. In response to the zona pellucida phosphorylationrdephosphorylation reactions may switch the sperm from the steady to the active state. By interacting with the capacitated sperm the clustered presentation of the oligosaccharide chains within the three-dimensional structure of the zona pellucida may initiate the formation of a multimeric receptor complex within the sperm membrane, thereby aggregating the signaling molecules of the complex that then trigger the cascade leading to acrosomal exocytosis, zona penetration and fusion with the egg.
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Yonezawa, N., Aoki, H., Hatanaka, Y., Nakano, M., 1995. Involvement of N-linked carbohydrate chains of pig zona pellucida in sperm–egg binding. Eur. J. Biochem. 233, 35–41. Yonezawa, N., Fukui, N., Kudo, K., Nakano, M., 1999. Localization of neutral N-linked carbohydrate chains in pig zona pellucida glycoprotein ZPC. Eur. J. Biochem. 260, 57–63. Yurewicz, E.C., Pack, B.A., Sacco, A.G., 1991. Isolation, composition and biological activity of sugar chains of porcine zona pellucida 55K glycoproteins. Mol. Reprod. Dev. 30, 126–134. Yurewicz, E.C., Sacco, A.G., Gupta, S.K., Naxing, X., Gage, D.A., 1998. Hetero-oligomerisation-dependent binding of pig oocyte zona pellucida glycoproteins ZPB and ZPC to boar sperm membrane vesicles. J. Biol. Chem. 273, 7488–7494.
Oocyte–sperm interactions ) Edda Topfer-Petersen , Anna M. Petrounkina, ¨ Mahnaz Ekhlasi-Hundrieser Institute of ReproductiÕe Medicine, School of Veterinary Medicine, Bunteweg 15, ¨ D-30559 HannoÕer, Germany
Abstract The penetration of the zona pellucida is a crucial step during fertilization. Spermatozoa that are unable to recognize and bind to the zona pellucida glycoproteins or respond to the zona pellucida by undergoing the acrosome reaction fail to fertilize the egg. In most mammalian species, after entering the fallopian tube sperm are stored in the isthmic part of the oviduct under conditions that maintain sperm viability and synchronize both sperm transport and the process of acquisition of fertilizing ability, called capacitation. Only capacitated sperm are enabled to recognize the oocyte and respond to the oocyte signals in an appropriate manner. Close to time of ovulation sperm are released from the oviductal epithelium and swim to site of fertilization. The oviduct and the oocyte itself appear to coordinate sperm function and gamete interaction. The gamete recognition and the next levels of interaction are probably granted by the carbohydrate–protein interactions. Upon binding the signal cascade leading to acrosomal exocytosis is activated, eventually initiated by aggregation of zona pellucida receptor molecules. These signal transducing mechanisms are primed during the capacitation process. Tyrosine phosphorylation, tightly connected to the cholesterol efflux from the plasma membrane, and hyperpolarization seem be involved in this priming by activation of Ca2q pathways. Further preparational steps of the acrosome reaction may be mediated by osmosensitive signal transducing mechanisms. The current perspective focuses on the molecules involved in the complex hierarchy of sperm–egg interactions and regulative events priming sperm cell during capacitation for the acrosome reaction. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Sperm; Egg; Gamete recognition; Carbohydrate–protein interaction; Capacitation; Acrosome reaction
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Corresponding author. Tel.: q49-511-9538520; fax: q49-51-9538504. .. E-mail address: [email protected] ŽE. Topfer-Petersen ¨
0378-4320r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0 3 7 8 - 4 3 2 0 Ž 0 0 . 0 0 1 2 8 - 7
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1. Introduction The penetration of the oocyte zona pellucida is a crucial step during fertilization. The zona pellucida is the extracellular network-like matrix enveloping the egg that protects the growing egg and the preimplantation embryo against physical damages. Sperm that are unable to recognize and bind to the zona pellucida glycoproteins, as well as sperm, upon binding, that are unable to respond with it by undergoing the acrosome reaction fail to fertilize the egg. After entering the Fallopian tube sperm are stored in the isthmic part of the oviduct by binding to the ciliated cell lining the oviductal epithelium ŽSuarez, 1999.. Sperm are stored under conditions that maintain sperm viability and synchronize sperm transport and the capacitating process. This enables sperm to interact with the oocyte in the appropriate manner. Reaching the site of fertilization sperm recognize the egg by carbohydrate–protein interactions. It is well accepted that the corresponding carbohydrate-binding proteins of the sperm surface bind defined oligosaccharide ligands of the zona pellucida. Upon binding the signaling cascade leading to the acrosomal exocytosis Žacrosome reaction. is activated. This allows sperm to penetrate the zona pellucida. After penetrating the zona pellucida sperm interact and fuse with egg vitelline membrane and trigger thus the embryonic development program ŽYanagimachi, 1994.. The current perspective focuses on the molecules involved in the complex hierarchy of interactions between sperm and egg in pig and other domestic animals.
2. Molecules involved in gamete recognition Close to the time of ovulation sperm are released from the oviductal epithelium and swim to the site of fertilization to meet the egg. The hyperactivated motility that sperm develop during the capacitating process not only enables the sperm to reach the oocyte but also may be necessary for the collision with the egg assisting the manifestation of the adhesion between sperm and egg ŽThaler and Cardullo, 1996.. The adhesion between both gametes is a complex sequence of binding events implicating low and high affinity binding sites ŽThaler and Cardullo, 1996.. The fundamental mechanism of gamete recognition appears to be conserved throughout the evolution from marine invertebrates to eutherian mammals and is based on carbohydrate–protein interactions between the sperm and the oocyte envelope. Oligosaccharides that are presented with a certain arrangement within the supramolecular architecture of the egg envelope are recognized by complementary carbohydrate receptors of the sperm, thereby mediating gamete recognition and coordinating sperm functions to warrant fertilization.
3. Zona pellucida The mammalian zona pellucida is composed of three glycoproteins that are products of the three zona pellucida genes named according to their length: ZPA, ZPB and ZPC
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genes ŽHarris et al., 1994.. In rodents zp glycoproteins are exclusively synthesized by the oocyte whereas, in domestic animals possessing a thick zona pellucida, e.g. in pig and cow, during follicular development the surrounding follicle cells contribute to the formation of the extra cellular matrix Žfor review see Sinowatz et al., 1999.. The three proteins build a typical fibrogranular structure by noncovalent interactions presenting a complex and highly heterogeneous mixture of asparagine ŽN.- and serinerthreonine ŽO.-linked oligosaccharide side chains. It has been proved that in different mammalian species amino acid sequence of the zp glycoproteins is highly conserved between different mammalian species. However, variable posttranslational glycosylation and processing of the polypeptide chains as well as the variable assembling of the supramolecular structure of the zp matrix Žpossibly due to differing biosynthetic pathways. lead to substantial differences of zp structure and function between rodents Žmouse. and domestic animals Žpig.. In mouse the zona pellucida protein 3 ŽmZP3 encoded by the ZPC gene. carrying the sperm receptor activity and the acrosome reaction-inducing potency forms together with zona pellucida protein 2 ŽmZP2 encoded by the ZPA gene. long periodically heterodimeric filaments that are randomly interconnected with the zona pellucida protein 1 ŽmZP1 encoded by the ZPB gene. ŽWassarman and Mortillo, 1991.. In contrast, in pig the biological active zp protein has been found to be ZPB Žthe mZP1 homologue. that tends to aggregate with ZPC Žthe mZP3 homologue. thereby increasing the sperm binding capacity ŽYurewicz et al., 1998.. Murine zp proteins can be separated by SDS-PAGE showing molecular masses of 80 kDa ŽZP3rZPC., 120 kDa ŽZP2rZPA. and 220 kDa ŽZP1ŽZPB. Žreviewed by Wassarman, 1999.. In pig the zona pellucida protein 3 ŽpZP3. has been shown to be a mixture of the so-called pZP3a ŽZPB. and pZP3b ŽZPB. with apparent molecular masses of 55 kDa and in cow the ZP3arb homologues reveal overlapping bands Ž78–88 kDa. after 2-D PAGE ŽNoguchi and Nakano, 1992; Topper et al., 1997.. Information on the oligosaccharide structure of zp glycoproteins is almost complete for pig and partially available for mouse and cow ŽHokke et al., 1994; Nakano et al., 1996; Topfer-Petersen, 1999.. Although the ¨ structures of the oligosaccharide chains are basically the same in these three species, they differ in the percentage and structure of the neutral N-linked carbohydrates. Whereas, in mouse the N-glycans are almost acidic, the major neutral N-glycans Žabout 25%. of the porcine zp glycoproteins belong to the bi-antennary fucosylated complex N-type and is a high mannose-type in cattle. In cattle the major neutral N-glycan has been implicated in sperm–egg recognition ŽNakano et al., 1996. and may bind to still poorly described mannose-binding proteins of the capacitated sperm ŽSuarez, personal communication.. In pig sperm receptor activity has been mapped to O- and N-linked glycans of ZPB ŽYurewicz et al., 1991; Yonezawa et al., 1995.. The trirtetra-antennary N-glycans localized in the N-terminal region of the mature ZPB ŽpZP3a . mediate the binding of sperm to the zona pellucida whereas, the structural identical trirtetra-antennary N-glycans of the ZPC molecule ŽpZP3b . appear to play no role in gamete recognition ŽKudo et al., 1998, Yonezawa et al., 1999.. The only difference between these oligosaccharides is the C-terminally localized glycosylation site within the ZPC molecule, possibly leading to a reduced accessibility of the glycan chains, dependent on folding of the protein ŽFig. 1.. This observation emphasizes that the assembling of the zp glycoproteins and the correct presentation of the biological active oligosaccharides
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Fig. 1. Schematic presentation of the known N-glycosylation sites in porcine zp glycoproteins. Of the six potential N-glycosylation sites of ZPA only Asn268 has been identified carrying biantennary N-glycans ŽTopfer-Petersen, unpublished.. ZPB and ZPC both possess three glycosylation sites ŽKudo et al., 1998; ¨ Yonezawa et al., 1999.. The mature ZPB molecule is N-terminally processed ŽAsp 137. and the mature ZPC molecule losses the signal peptide and is N-terminally blocked Žpyro-Gln23.. Signal peptide is marked in grey.
within the three-dimensional structure are important features to achieve the physiological relevant binding between both gametes. In mouse low- and high-affinity binding sites have been identified on the sperm surface implicating a hierarchy of binding events ŽJohnston et al., 1998.. Interestingly, the high-affinity site recognizing fucosylated oligosaccharides can be occupied with less affinity by other carbohydrate structures. The multivalent presentation of the biological active oligosaccharides may be a necessity to create high-affinity binding. In mouse the relevant O-linked oligosaccharides are clustered at the C-terminal sperm-combing sites of mZPC Žreviewed by Wassarman, 1999.. In pig the arrangement of the oligosaccharides within the heteromultimeric ZPBrZPC complex may be responsible for the manifestation of high-affinity binding to the sperm ŽYurewicz et al., 1998.. There is a considerable controversy regarding the structural entity of the sperm oligosaccharide ligands in both species suggesting that Ži. different experimental conditions Žand the possible binding of uncapacitated and capacitated sperm to the zona; Miranda, 1998. andror Žii. an allowed structural variety of the presented carbohydrates at the sperm-binding site of the intact zona pellucida may account for these differences.
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4. Zona pellucida binding proteins A long list of putative zona pellucida receptors has been described up to date. However, only few are characterized regarding their carbohydrate specificity and structure of the carbohydrate-binding domain, e.g. rabbit sp17, mouse galactosyltransferase, porcine spermadhesins and proracrosin. Spermadhesins represent a new class of lectins with specificity to galactose-containing structures, mannose or mannose-6-phosphate, whereas, proacrosin binds to zp glycoproteins following a sulfate-recognition mechanism. Similarly, sp17 recognizes sulfated carbohydrate as they are presented in the zona pellucida and fucoidan and share consensus sequences with the class of C-type lectins. Porcine zonadhesin and mouse sp56 are proteins containing a molecular structure with still unknown ligand-binding specificity. Zona receptor kinases Žmouse p95 and human hu9. ZRK and human fertility antigen A-1 ŽFA-1. are autophosphorylated in response to the zona pellucida exhibiting an intrinsic signaling potential. Some proteins have been found by targeted mutagenesis not to be particularly relevant to gamete recognition Že.g. mouse galactosyltransferase.. They may rather function in earlier events such as capacitating and sperm–oviduct interactions Žspermadhesins.. Others are obviously located in the wrong compartment of the sperm to participate in gamete recognition or primary binding Že.g. proracrosin and PH-20.. These may rather be involved in the transient secondary binding of acrosome-reacted sperm during zona penetration Žreviewed by Naz Rajesh, 1996; McLesky et al., 1998; Shur, 1998; Topfer¨ Petersen, 1999..
5. Receptor aggregation initiates acrosome reaction The first evidence that the aggregation of zona pellucida receptor molecules within the plane of the sperm membrane triggers the signaling cascade resulting in acrosome reaction was demonstrated by Leyton and Saling Ž1989.. Zp glycoproteins and antibodies directed against zona receptor kinase ŽZRK., galactosyltransferase and some other sperm surface proteins are able to initiate the acrosome reaction whereas, a zp glycopeptide fraction retaining sperm binding ability and univalent Fab-fragments fail to induce the acrosome reaction ŽMcLesky et al., 1998; Shur, 1998.. Putative zona pellucida binding proteins have been found to traverse the sperm plasma membrane as ZRK, galactosyltransferase, human FA-1 and porcine zonadhesin whereas, porcine p47, spermadhesins and murine proteinase inhibitor-binding protein are peripherally associated to the sperm surface ŽAarons et al., 1991; Naz Rajesh, 1996; McLesky et al., 1998; Shur, 1998; Topfer-Petersen, 1999.. Those surface-associated and transmembrane pro¨ teins may form the multimeric receptor upon binding to the zona pellucida thus initiating the aggregation of the signaling molecules of the receptor complex ŽZRK, galactosyltransferase, zonadhesin or other still unknown components. that then trigger the different pathways of acrosome reaction ŽFlorman et al., 1998.. The postulated multimeric sperm receptor ŽShur, 1998. may be composed by a varying set of proteins without loosing completely the ability to initiate recognition and to trigger the acrosome.
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The following model of the ionic events in ZP signal transduction is largely based on the information reviewed by Florman et al. Ž1998.. According to this model the activation of the sperm surface receptor by the association with mouse ZP3 initiates two separate pathways. One signaling sequence leads to the activation of a cation channel C producing inward currents depolarizing sperm membrane potential and opening low voltage-activated T-type Ca2q channel. The other pathway initiates internal alkalinization by mechanisms likely reflecting the mediation of G proteins. This pH increase and transient Ca2q current in response to ZP or membrane depolarization promote a sustained Ca2q increase. The elevation of Ca2q level, a rise of intracellular pH and the enhancement of membrane fusogenity are postulated to be the driving forces triggering the cascade of acrosomal expcytosis ŽHarrison and Roldan, 1990; Roldan and Harrison, 1990; Kopf and Gerton, 1991; Aitken, 1997..
6. Priming of signal transducing mechanisms during capacitation Ejaculated mammalian sperm need a period of incubation in the female reproductive tract in order to acquire the capacity to fertilize an egg ŽYanagimachi, 1994.. This period of attaining functional competence, referred to as capacitation ŽAustin, 1951., is required for undergoing the acrosome reaction induced by physiological stimuli such as ZP ŽFlorman and First, 1988.. Since the response to the oocyte signals can be initiated only in capacitated sperm, the signal-transducing mechanisms appear to be primed during capacitation. Capacitation is accompanied by an increase of membrane fluidity and remodeling of the sperm surface, protein phosphorylation, an increase of internal Ca2q and pH and membrane hyperpolarization ŽStorey, 1995.. Generally accepted is the concept of capacitation as series of positive destabilizing events ŽHarrison, 1996.. The initial event is the BSArLDH-mediated cholesterol efflux resulting in an increase of plasma membrane fluidity thus supporting membrane remodeling ŽDavis et al., 1979; Visconti et al., 1999.. Kinase-mediated tyrosine posphorylations are tightly connected with this event ŽVisconti et al., 1994a,b.. Tyrosine phosphorylation appears to be an essential process of capacitation: if tyrosine kinase inhibitors block it the spermatozoa lose the ability to respond to physiological agonists ŽAitken et al., 1996.. Since cross talk with cAMP is involved in the regulation of protein tyrosine phosphorylation, it is tempting to speculate that the loss of cholesterol may be involved in the regulation of cAMP pathway. The monotonic elevating of Ca2q with the rate about 0.5 nmrmin seems to be insufficient to initiate acrosome reaction and might occur due to the modulation of Ca2q-ATPase activity. The mechanism related to voltage-dependent T-channel described above ŽFlorman et al., 1998 and references therein. appears to be responsible for the explosive increase of Ca2q in response to physiological agonists leading to the acrosomal exocytosis. The sperm T-channel may be primed and held in steady state during capacitating by hyperpolarization Žprobably due to Kq-permeability contribution. at the level of an upstream action channel and by tyrosine phosphorylation. The tyrosine phosphorylation of T-channel or channel regulator decreases Ca2q current through the channel prevent-
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ing the acrosome reaction, whereas, the dephosphorylation may stimulate the activation of the channel ŽArnoult et al., 1997.. However, it appears that further signal transduction mechanisms may be involved in the activation of Ca2q pathways. A mild hypoosmotic shock has been shown to be a potent stimulus of the acrosome reaction. Rossato et al. Ž1996. demonstrated that human spermatozoa possess Ca2q influx pathways activated by plasma membrane stretching. A blocker of mechano-sensitive Ca2q channels ŽGdq. diminished osmotically sensitive Ca2q-rises in a dose-dependent manner and completely blocked the osmotically sensitive acrosome reaction. The formal evidence is missing that Ca2q rise occurs via Ca2q channels, but this hypothesis seems likely due to fast kinetics, sensitivity to membrane depolarization and Gdq treatment. Osmosensitive mechanisms may also play a role during preparation steps of the acrosome reaction Žcapacitation.. The regulation mediated by osmotic events may be reflected in cell volume behavior during capacitation. Boar sperm cell volume tends to show cyclical variations during incubation under capacitating conditions with the frequency varying dependent on the incubation conditions. The expression of different levels of swelling at fixed osmotic conditions is coupled to the change in cell osmole content. The osmosensing regulatory performance, such as swelling and subsequent regulatory volume decrease, could be modulated during capacitation and may reflect the ongoing destabilization of the membrane on earlier stages of capacitation treatment ŽPetrounkina et al., 2000.. Preliminary studies on boar sperm let suggest that Ži. changes in cell volume are closely related to the expression of tyrosine phosphorylation as shown by indirect immunfluorescence on the earlier stages of incubation under capacitation conditions, and Žii. cell volume regulation is mediated in the first line by quinine-sensitive channels ŽPetrounkina et al., 2000.. The participation of quinine-sensitive channels on cell volume regulation of bull sperm was reported by Kulkarni et al. Ž1997.. For other cell types Že.g. in erythrocytes. protein tyrosine phosphorylation has already been found to be osmo- and volume-sensitive ŽMush et al., 1994, 1998.. Hypoosmotic shock triggered a rapid increase in tyrosine phosphorylation; furthermore, the volume regulation of swollen cells was sensitive to tyrosine phosphatase inhibition. Phosphorylation of a band 3 protein in human erythrocytes, observed by ionophore treatment or shrinkinginduced volume regulation, was suppressed by quinine, an inhibitor of Ca2q-activated Kq channel ŽMinetti et al., 1996.. Moving into field of speculation, the similar modulation of osmosensing signal transduction by tyrosine phosphorylation may be expected also in sperm cells while priming for activation in response to ZP and for zona penetration. Further studies are in progress to investigate this hypothetical regulatory mechanism of signal transduction during capacitation.
7. Conclusion During the capacitating process several of regulative events including osmo-sensitive mechanisms appear to prime the sperm cell awaiting the oocyte signals to enter an
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activated stage and be able to fertilize the egg. In response to the zona pellucida phosphorylationrdephosphorylation reactions may switch the sperm from the steady to the active state. By interacting with the capacitated sperm the clustered presentation of the oligosaccharide chains within the three-dimensional structure of the zona pellucida may initiate the formation of a multimeric receptor complex within the sperm membrane, thereby aggregating the signaling molecules of the complex that then trigger the cascade leading to acrosomal exocytosis, zona penetration and fusion with the egg.
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Yonezawa, N., Aoki, H., Hatanaka, Y., Nakano, M., 1995. Involvement of N-linked carbohydrate chains of pig zona pellucida in sperm–egg binding. Eur. J. Biochem. 233, 35–41. Yonezawa, N., Fukui, N., Kudo, K., Nakano, M., 1999. Localization of neutral N-linked carbohydrate chains in pig zona pellucida glycoprotein ZPC. Eur. J. Biochem. 260, 57–63. Yurewicz, E.C., Pack, B.A., Sacco, A.G., 1991. Isolation, composition and biological activity of sugar chains of porcine zona pellucida 55K glycoproteins. Mol. Reprod. Dev. 30, 126–134. Yurewicz, E.C., Sacco, A.G., Gupta, S.K., Naxing, X., Gage, D.A., 1998. Hetero-oligomerisation-dependent binding of pig oocyte zona pellucida glycoproteins ZPB and ZPC to boar sperm membrane vesicles. J. Biol. Chem. 273, 7488–7494.