Abstract
Successful mammalian fertilization results in the union of two gametes, a spermatozoon and a mature oocyte. Membrane fusion events are essential for at least two distinct steps of the fertilization process: (i) the vesiculation of the acrosomal surface membranes during sperm acrosomal exocytosis (AE), induced by sperm binding to the egg-coat, and (ii) fusion of the oocyte plasma membrane, the oolemma, with the sperm plasma membrane that occurs after AE and sperm-egg coat penetration. The rearrangement of sperm plasma membrane domains/membrane lipid raft formation during sperm capacitation in the female reproductive tract is a priming step that enables the fusion and vesiculation of outer acrosomal membranes during AE. The membrane fusion/vesiculation events of AE seem to share similarities with synaptic vesicle fusion, assisted by the membrane proteins of the SNARE hypothesis. The AE exposes the transmembrane receptors on the sperm head equatorial segment in preparation for sperm-oolemma adhesion and fusion. Gene ablation studies indicate that the tetraspanin family proteins CD9 and CD81 on the oolemma interact with the superglobulin family protein IZUMO on the sperm plasmalemma to mediate sperm-oolemma adhesion in mammals. The fusogenicity of IZUMO has not been established, so the involvement of this system in the actual membrane fusion part of sperm–oolemma interaction remains open. Interactions of ADAM family proteins on sperm plasma membrane with oolemma integrins appear non-essential during sperm-oolemma fusion, but integrins may play a supporting role via sustenance of the tetraspanin web in the oocyte cortex. Sperm-oolemma binding may be reinforced by a cast of other receptors found on the surface of the sperm head (e.g. CRISP and MN9). The present chapter reviews recent progress in the study of these fundamental factors of gamete membrane fusion during mammalian fertilization.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- ADAM:
-
A disintegrin and a metalloprotease
- AE:
-
Acrosomal exocytosis
- AFAF:
-
Acrosome formation associated factor
- CD:
-
Cluster of differentiation
- CEA:
-
Carcinoembryonic antigen
- CRISP:
-
Cysteine-rich secretory protein
- IAM:
-
Inner acrosomal membrane
- ICSI:
-
Intracytoplasmic sperm injection
- IgSF:
-
Immunoglobulin superfamily (protein)
- KO:
-
Knock-out
- LEL:
-
Large extracellular loop
- NSF:
-
N-ethylmaleimide-sensitive factor
- OAM:
-
Outer acrosomal membrane
- PVS:
-
Perivitelline space
- PSG:
-
Pregnancy-specific glycoprotein
- PM:
-
Plasma membrane
- PTGFRN:
-
Prostaglandin F2 receptor negative regulator
- PTP:
-
Protein tyrosine phosphatase
- SEL:
-
Small extracellular loop
- SNAP:
-
Soluble NSF attachment protein
- SNARE:
-
SNAP receptors
- t-SNARE:
-
Target-SNARE
- VAMP:
-
Vesicle associated membrane protein
- v-SNARE:
-
Vesicle-SNARE
- ZP:
-
Zona pellucida
References
Almeida EA, Huovila AP, Sutherland AE et al (1995) Mouse egg integrin alpha 6 beta 1 functions as a sperm receptor. Cell 81:1095–1104
Andria ML, Barsh GS, Levy S (1992) Expression of TAPA-1 in preimplantation mouse embryos. Biochem Biophys Res Commun 186:1201–1206
Aricescu AR, Jones EY (2007) Immunoglobulin superfamily cell adhesion molecules: zippers and signals. Curr Opin Cell Biol 19:543–550
Baessler KA, Lee Y, Sampson NS (2009) Beta1 integrin is an adhesion protein for sperm binding to eggs. ACS Chem Biol 4:357–366
Barclay AN (2003) Membrane proteins with immunoglobulin-like domains–a master superfamily of interaction molecules. Semin Immunol 15:215–223
Barraud-Lange V, Naud-Barriant N, Bomsel M et al (2007) Transfer of oocyte membrane fragments to fertilizing spermatozoa. FASEB J 21:3446–3449
Bedford JM, Cooper GW (1978) Membrane fusion events in the fertilization of vertebrate eggs. In: Poste G, Nicolson GL (eds) Membrane fusion, vol 5. Elsevier/North-Holland Biomedical Press, Amsterdam
Bennett MK, Calakos N, Scheller RH (1992) Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 257:255–259
Bigler D, Takahashi Y, Chen MS et al (2000) Sequence-specific interaction between the disintegrin domain of mouse ADAM 2 (fertilin beta) and murine eggs. Role of the alpha(6) integrin subunit. J Biol Chem 275:11576–11584
Boucheix C, Rubinstein E (2001) Tetraspanins. Cell Mol Life Sci 58:1189–1205
Breitbart H (2002) Role and regulation of intracellular calcium in acrosomal exocytosis. J Reprod Immunol 53:151–159
Buffone MG, Foster JA, Gerton GL (2008) The role of the acrosomal matrix in fertilization. Int J Dev Biol 52:511–522
Busso D, Goldweic NM, Hayashi M et al (2007) Evidence for the involvement of testicular protein CRISP2 in mouse sperm-egg fusion. Biol Reprod 76:701–708
Cal S, Freije JM, Lopez JM et al (2000) ADAM 23/MDC3, a human disintegrin that promotes cell adhesion via interaction with the alphavbeta3 integrin through an RGD-independent mechanism. Mol Biol Cell 11:1457–1469
Campbell KD, Reed WA, White KL (2000) Ability of integrins to mediate fertilization, intracellular calcium release, and parthenogenetic development in bovine oocytes. Biol Reprod 62:1702–1709
Charrin S, Le Naour F, Labas V et al (2003) EWI-2 is a new component of the tetraspanin web in hepatocytes and lymphoid cells. Biochem J 373: 409–421
Charrin S, le Naour F, Silvie O et al (2009) Lateral organization of membrane proteins: tetraspanins spin their web. Biochem J 420:133–154
Chen H, Sampson NS (1999) Mediation of sperm-egg fusion: evidence that mouse egg alpha6beta1 integrin is the receptor for sperm fertilinbeta. Chem Biol 6:1–10
Chen MS, Almeida EA, Huovila AP et al (1999a) Evidence that distinct states of the integrin alpha6beta1 interact with laminin and an ADAM. J Cell Biol 144:549–561
Chen MS, Tung KS, Coonrod SA et al (1999b). Role of the integrin-associated protein CD9 in binding between sperm ADAM 2 and the egg integrin alpha6beta1: implications for murine fertilization. Proc Natl Acad Sci USA 96:11830–11835
Chen YA, Scheller RH (2001) SNARE-mediated membrane fusion. Nat Rev Mol Cell Biol 2:98–106
Cho C, Bunch DO, Faure JE et al (1998) Fertilization defects in sperm from mice lacking fertilin beta. Science 281:1857–1859
Da Ros VG, Maldera JA, Willis WD et al (2008) Impaired sperm fertilizing ability in mice lacking Cysteine-RIch Secretory Protein 1 (CRISP1). Dev Biol 320:12–18
De Blas GA, Roggero CM, Tomes CN et al (2005) Dynamics of SNARE assembly and disassembly during sperm acrosomal exocytosis. PLoS Biol 3:e323
Delaguillaumie A, Lagaudriere-Gesbert C, Popoff MR et al (2002) Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes. J Cell Sci 115:433–443
Ellerman DA, Ha C, Primakoff P et al (2003) Direct binding of the ligand PSG17 to CD9 requires a CD9 site essential for sperm-egg fusion. Mol Biol Cell 14:5098–5103
Ellerman DA, Pei J, Gupta S et al (2009) Izumo is part of a multiprotein family whose members form large complexes on mammalian sperm. Mol Reprod Dev 76:1188–1199
Eto K, Puzon-McLaughlin W, Sheppard D et al (2000) RGD-independent binding of integrin alpha9beta1 to the ADAM-12 and -15 disintegrin domains mediates cell–cell interaction. J Biol Chem 275:34922–34930
Evans JP (2001) Fertilin beta and other ADAMs as integrin ligands: insights into cell adhesion and fertilization. Bioessays 23:628–639
Evans JP, Kopf GS, Schultz RM (1997) Characterization of the binding of recombinant mouse sperm fertilin beta subunit to mouse eggs: evidence for adhesive activity via an egg beta1 integrin-mediated interaction. Dev Biol 187:79–93
Evans JP, Schultz RM, Kopf GS (1995) Identification and localization of integrin subunits in oocytes and eggs of the mouse. Mol Reprod Dev 40:211–220
Evans JP, Schultz RM, Kopf GS (1998) Roles of the disintegrin domains of mouse fertilins alpha and beta in fertilization. Biol Reprod 59:145–152
Feigelson SW, Grabovsky V, Shamri R et al (2003) The CD81 tetraspanin facilitates instantaneous leukocyte VLA-4 adhesion strengthening to vascular cell adhesion molecule 1 (VCAM-1) under shear flow. J Biol Chem 278:51203–51212
Foster JA, Friday BB, Maulit MT (1997) 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 272:12714–12722
Gadella BM, Visconti PE (2006). Regulation of capacitation. In: De Jonge C, Barratt CL (eds) The sperm cell. Cambridge University Press, Cambridge, UK, pp 134–169
Gerst JE (1999) SNAREs and SNARE regulators in membrane fusion and exocytosis. Cell Mol Life Sci 55:707–734
Glazar AI, Evans JP (2009) Immunoglobulin superfamily member IgSF8 (EWI-2) and CD9 in fertilisation: evidence of distinct functions for CD9 and a CD9-associated protein in mammalian sperm-egg interaction. Reprod Fertil Dev 21:293–303
Gould RJ, Polokoff MA, Friedman PA et al (1990) Disintegrins: a family of integrin inhibitory proteins from viper venoms. Proc Soc Exp Biol Med 195:168–171
He ZY, Brakebusch C, Fassler R et al (2003) None of the integrins known to be present on the mouse egg or to be ADAM receptors are essential for sperm-egg binding and fusion. Dev Biol 254:226–237
He ZY, Gupta S, Myles D et al (2009) Loss of surface EWI-2 on CD9 null oocytes. Mol Reprod Dev 76:629–636
Hemler ME (2003) Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol 19:397–422
Higginbottom A, Takahashi Y, Bolling L et al (2003) Structural requirements for the inhibitory action of the CD9 large extracellular domain in sperm/oocyte binding and fusion. Biochem Biophys Res Commun 311:208–214
Hohne-Zell B, Gratzl M (1996) Adrenal chromaffin cells contain functionally different SNAP-25 monomers and SNAP-25/syntaxin heterodimers. FEBS Lett 394:109–116
Hu XQ, Ji SY, Li YC et al (2009) Acrosome formation-associated factor is involved in fertilization. Fertil Steril 93:1482–1492
Inoue N, Ikawa M, Isotani A et al (2005) The immunoglobulin superfamily protein Izumo is required for sperm to fuse with eggs. Nature 434:234–238
Iwao Y, Fujimura T (1996) Activation of Xenopus eggs by RGD-containing peptides accompanied by intracellular Ca2+ release. Dev Biol 177:558–567
Kaji K, Oda S, Miyazaki S et al (2002) Infertility of CD9-deficient mouse eggs is reversed by mouse CD9, human CD9, or mouse CD81; polyadenylated mRNA injection developed for molecular analysis of sperm-egg fusion. Dev Biol 247:327–334
Kaji K, Oda S, Shikano T et al (2000) The gamete fusion process is defective in eggs of Cd9-deficient mice. Nat Genet 24:279–282
Kim KS, Cha MC, Gerton GL (2001a) Mouse sperm protein sp56 is a component of the acrosomal matrix. Biol Reprod 64:36–43
Kim KS, Foster JA, Gerton GL (2001b) Differential release of guinea pig sperm acrosomal components during exocytosis. Biol Reprod 64:148–156
Kim KS, Gerton GL (2003) Differential release of soluble and matrix components: evidence for intermediate states of secretion during spontaneous acrosomal exocytosis in mouse sperm. Dev Biol 264:141–152
Kolesnikova TV, Stipp CS, Rao RM et al (2004) EWI-2 modulates lymphocyte integrin alpha4beta1 functions. Blood 103:3013–3019
Lammerding J, Kazarov AR, Huang H et al (2003) Tetraspanin CD151 regulates alpha6beta1 integrin adhesion strengthening. Proc Natl Acad Sci USA 100:7616–7621
Le Naour F, Rubinstein E, Jasmin C et al (2000) Severely reduced female fertility in CD9-deficient mice. Science 287:319–321
Lefevre B, Wolf JP, Ziyyat A (2010) Sperm-egg interaction: is there a link between tetraspanin(s) and GPI-anchored protein(s)? Bioessays 32:143–152
Levy S, Shoham T (2005) The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol 5:136–148
Li YC, Hu XQ, Zhang KY et al (2006) Afaf, a novel vesicle membrane protein, is related to acrosome formation in murine testis. FEBS Lett 580:4266–4273
Linder B, Heinlein UA (1997) Decreased in vitro fertilization efficiencies in the presence of specific cyritestin peptides. Dev Growth Differ 39:243–247
Linfor J, Berger T (2000) Potential role of alphav and beta1 integrins as oocyte adhesion molecules during fertilization in pigs. J Reprod Fertil 120:65–72
Maleszewski M, Kimura Y, Yanagimachi R (1996) Sperm membrane incorporation into oolemma contributes to the oolemma block to sperm penetration: evidence based on intracytoplasmic sperm injection experiments in the mouse. Mol Reprod Dev 44:256–259
Manandhar G, Toshimori K (2001) Exposure of sperm head equatorin after acrosome reaction and its fate after fertilization in mice. Biol Reprod 65:1425–1436
Miller BJ, Georges-Labouesse E, Primakoff P et al (2000) Normal fertilization occurs with eggs lacking the integrin alpha6beta1 and is CD9-dependent. J Cell Biol 149:1289–1296
Miyado K, Yamada G, Yamada S et al (2000) Requirement of CD9 on the egg plasma membrane for fertilization. Science 287:321–324
Miyado K, Yoshida K, Yamagata K et al (2008) The fusing ability of sperm is bestowed by CD9-containing vesicles released from eggs in mice. Proc Natl Acad Sci USA 105:12921–12926
Nath D, Slocombe PM, Stephens PE et al (1999) Interaction of metargidin (ADAM-15) with alphavbeta3 and alpha5beta1 integrins on different haemopoietic cells. J Cell Sci 112:579–587
Nath D, Slocombe PM, Webster A et al (2000) Meltrin gamma(ADAM-9) mediates cellular adhesion through alpha(6)beta(1 )integrin, leading to a marked induction of fibroblast cell motility. J Cell Sci 113:2319–2328
Neilson L, Andalibi A, Kang D et al (2000) Molecular phenotype of the human oocyte by PCR-SAGE. Genomics 63:13–24
Nishiuchi R, Sanzen N, Nada S et al (2005) Potentiation of the ligand-binding activity of integrin alpha3beta1 via association with tetraspanin CD151. Proc Natl Acad Sci USA 102:1939–1944
Novick P, Zerial M (1997) The diversity of Rab proteins in vesicle transport. Curr Opin Cell Biol 9:496–504
Okabe M, Adachi T, Takada K et al (1987) Capacitation-related changes in antigen distribution on mouse sperm heads and its relation to fertilization rate in vitro. J Reprod Immunol 11:91–100
Olson GE, Winfrey VP (1994) Structure of acrosomal matrix domains of rabbit sperm. J Struct Biol 112:41–48
Oura C, Toshimori K (1990) Ultrastructural studies on the fertilization of mammalian gametes. Int Rev Cytol 122:105–151
Oyler GA, Higgins GA, Hart RA et al (1989) The identification of a novel synaptosomal-associated protein, SNAP-25, differentially expressed by neuronal subpopulations. J Cell Biol 109:3039–3052
Ramalho-Santos J, Moreno RD, Sutovsky P et al (2000) SNAREs in mammalian sperm: possible implications for fertilization. Dev Biol 223:54–69
Rochwerger L, Cohen DJ, Cuasnicu PS (1992) Mammalian sperm-egg fusion: the rat egg has complementary sites for a sperm protein that mediates gamete fusion. Dev Biol 153:83–90
Rochwerger L, Cuasnicu PS (1992) Redistribution of a rat sperm epididymal glycoprotein after in vitro and in vivo capacitation. Mol Reprod Dev 31:34–41
Rothman JE (1994) Mechanisms of intracellular protein transport. Nature 372:55–63
Rubinstein E, Le Naour., Lagaudriere-Gesbert C et al (1996) CD9, CD63, CD81, and CD82 are components of a surface tetraspan network connected to HLA-DR and VLA integrins. Eur J Immunol 26:2657–2665
Rubinstein E, Ziyyat A, Prenant M et al (2006) Reduced fertility of female mice lacking CD81. Dev Biol 290:351–358
Runge KE, Evans JE, He ZY et al (2007) Oocyte CD9 is enriched on the microvillar membrane and required for normal microvillar shape and distribution. Dev Biol 304:317–325
Sala-Valdes M, Ursa A, Charrin S et al (2006) EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin-radixin-moesin proteins. J Biol Chem 281:19665–19675
Schulz JR, Wessel GM, Vacquier VD (1997) The exocytosis regulatory proteins syntaxin and VAMP are shed from sea urchin sperm during the acrosome reaction. Dev Biol 191:80–87
Shamsadin R, Adham IM, Nayernia K, Heinlein UA, Oberwinkler H, Engel W (1999) Male mice deficient for germ-cell cyritestin are infertile. Biol Reprod 61:1445–1451.
Shilling FM, Magie CR, Nuccitelli R (1998) Voltage-dependent activation of frog eggs by a sperm surface disintegrin peptide. Dev Biol 202:113–124
Stein KK, Primakoff P, Myles D (2004) Sperm-egg fusion: events at the plasma membrane. J Cell Sci 117:6269–6274
Stipp CS, Kolesnikova TV, Hemler ME (2001) EWI-2 is a major CD9 and CD81 partner and member of a novel Ig protein subfamily. J Biol Chem 276:40545–40554
Suarez S (2002) Gamete transport. In: Hardy D (ed) Fertilization. Academic Press, San Diego, pp 3–28
Sutton-Smith M, Wong NK, Khoo KH et al (2007) Analysis of protein-linked glycosylation in a sperm-somatic cell adhesion system. Glycobiology 17:553–567
Takahashi Y, Bigler D, Ito Y et al (2001) Sequence-specific interaction between the disintegrin domain of mouse ADAM 3 and murine eggs: role of beta1 integrin-associated proteins CD9, CD81, and CD98. Mol Biol Cell 12:809–820
Takahashi Y, Yamakawa N, Matsumoto K et al (2000) Analysis of the role of egg integrins in sperm-egg binding and fusion. Mol Reprod Dev 56:412–423
Tarone G, Russo MA, Hirsch E et al (1993) Expression of beta 1 integrin complexes on the surface of unfertilized mouse oocyte. Development 117:1369–1375
Terrian DM, White MK (1997) Phylogenetic analysis of membrane trafficking proteins: a family reunion and secondary structure predictions. Eur J Cell Biol 73:198–204
Tomes CN, Michaut M, De Blas G et al (2002) SNARE complex assembly is required for human sperm acrosome reaction. Dev Biol 243:326–338
Toshimori K, Saxena DK, Tanii I et al (1998) An MN9 antigenic molecule, equatorin, is required for successful sperm-oocyte fusion in mice. Biol Reprod 59:22–29
Toshimori K, Tanii I, Araki S et al (1992) Characterization of the antigen recognized by a monoclonal antibody MN9: unique transport pathway to the equatorial segment of sperm head during spermiogenesis. Cell Tissue Res 270:459–468
van Goor H, Melenhorst WB, Turner AJ et al (2009) Adamalysins in biology and disease. J Pathol 219:277–286
Wang M, Lv Z, Shi J et al (2009) Immunocontraceptive potential of the Ig-like domain of Izumo. Mol Reprod Dev 76:794–801
Waterhouse R, Ha C, Dveksler GS (2002) Murine CD9 is the receptor for pregnancy-specific glycoprotein 17. J Exp Med 195:277–282
Weimbs T, Low SH, Chapin SJ et al (1997) A conserved domain is present in different families of vesicular fusion proteins: a new superfamily. Proc Natl Acad Sci USA 94:3046–3051
Weimbs T, Mostov K, Low SH et al (1998) A model for structural similarity between different SNARE complexes based on sequence relationships. Trends Cell Biol 8:260–262
Westbrook-Case VA, Winfrey VP, Olson GE (1995) Sorting of the domain-specific acrosomal matrix protein AM50 during spermiogenesis in the guinea pig. Dev Biol 167:338–349
Yamatoya K, Yoshida K, Ito C et al (2009) Equatorin: identification and characterization of the epitope of the MN9 antibody in the mouse. Biol Reprod 81:889–897
Yanagimachi R (1994) Mammalian fertilization. Raven Press, New York, NY
Yoshida K, Ito C, Yamatoya K et al (2009) A model of the acrosome reaction progression via the acrosomal membrane-anchored protein equatorin. Reproduction 139:533–544
Yuan R, Primakoff P, Myles DG (1997) A role for the disintegrin domain of cyritestin, a sperm surface protein belonging to the ADAM family, in mouse sperm-egg plasma membrane adhesion and fusion. J Cell Biol 137:105–112
Yunes R, Michaut M, Tomes C et al (2000) Rab3A triggers the acrosome reaction in permeabilized human spermatozoa. Biol Reprod 62:1084–1089
Zarelli VE, Ruete MC, Roggero CM et al (2009) PTP1B dephosphorylates N-ethylmaleimide-sensitive factor and elicits SNARE complex disassembly during human sperm exocytosis. J Biol Chem 284:10491–10503
Zerial M, McBride H (2001) Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2:107–117
Zhang XP, Kamata T, Yokoyama K et al (1998) Specific interaction of the recombinant disintegrin-like domain of MDC-15 (metargidin, ADAM-15) with integrin alphavbeta3. J Biol Chem 273:7345–7350
Zhou M, Graham R, Russell G et al (2001) MDC-9 (ADAM-9/Meltrin gamma) functions as an adhesion molecule by binding the alpha(v)beta(5) integrin. Biochem Biophys Res Commun 280:574–580
Ziyyat A, Rubinstein E, Monier-Gavelle F et al (2006) CD9 controls the formation of clusters that contain tetraspanins and the integrin alpha 6 beta 1, which are involved in human and mouse gamete fusion. J Cell Sci 119:416–424
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Yi, YJ., Zimmerman, S.W., Sutovsky, P. (2011). Gamete Binding and Fusion. In: Larsson, LI. (eds) Cell Fusions. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9772-9_8
Download citation
DOI: https://doi.org/10.1007/978-90-481-9772-9_8
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-90-481-9771-2
Online ISBN: 978-90-481-9772-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)