Signal Transduction in Mammalian Spermatozoa

  • G. S. Kopf
  • P. Kalab
  • P. Leclerc
  • X. P. Ning
  • D. Pan
  • P. Visconti
Conference paper
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 1)


Intercellular communication between gametes is essential to the unique event in the life cycle of an organism called fertilization. Achievement of successful fertilization results from requisite and reciprocal cell-induced sperm and egg activation events mediated by unique cellular and environmental cues associated with either the gametes or the reproductive tract/environment. In the case of the sperm, the interaction of this highly motile cell with the female reproductive tract/environment, as well as with the egg both at a distance and in close proximity, represent a series of integrated processes designed to deliver sperm with optimal fertilizing potential to the site of fertilization. Recent studies have revealed that many aspects of gamete activation prior and subsequent to fertilization have similarities to intercellular and intracellular signaling systems utilized by somatic cells. Cell surface receptors or binding proteins on sperm for egg products have been identified in some species, while their identity in other species remains controversial. The occupancy of these receptors/binding proteins by egg products results in trans-membrane signaling and stimulation of intracellular effector systems, leading to subsequent sperm activation. Such activation events may include changes in motility, chemotaxis, and induction of acrosomal exocytosis, all of which may be essential prerequisites to successful fertilization in various species. This review will summarize what is known about these intercellular communicative events, with an emphasis on the mechanisms by which mammalian sperm process egg-associated signals via signal transduction pathways to effect changes in cellular function. The nature of these signaling systems is now being elucidated at the molecular level and has revealed some unique aspects of communication and transmembrane signaling between gametes. An understanding of signal transduction in mammalian sperm will ultimately yield information about the nature of the receptors to which these signal transduction pathways are coupled, as well as the intracellular effectors that ultimately regulate sperm function. Moreover, an understanding of these regulatory pathways will be essential for the future development of clinical approaches designed to enhance or preclude fertilization.


Follicular Fluid Zona Pellucida Acrosome Reaction Sperm Function Mouse Sperm 
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  1. Arora KK, Fanccells: cloning, sequencing, and overexpression in active form of a full-length cDNA encoding a mitochondrial bindable form of hexokinase. J Biol Chem 265: 6481–6488Google Scholar
  2. Bentley JK, Garbers DL, Domino SE, Noland TD, VanDop C (1986) Spermatozoa contain a guanine nucleotide binding protein ADP-ribosylated by pertussis toxin. Biochem Biophys Res Commun 138: 728–734PubMedCrossRefGoogle Scholar
  3. Bleil JD, Wassarman PM (1980a) Structure and function of the zona pellucida: identification and characterization of the proteins of the mouse oocyte’s zona pellucida. Dev Biol 76: 185–202PubMedCrossRefGoogle Scholar
  4. Bleil JD, Wassarman PM (1980b) Synthesis of zona pellucida proteins by denuded and follicle-enclosed mouse oocytes during culture in vitro. Proc Natl Acad Sci USA 77: 1029–1033PubMedCrossRefGoogle Scholar
  5. Bleil JD, Wassarman PM (1983) Sperm-egg interactions in the mouse: sequence of events and induction of the acrosome reaction by a zona pellucida glycoprotein. Dev Biol 95: 317–324PubMedCrossRefGoogle Scholar
  6. Bled JD, Wassarman PM (1986) Autoradiographic visualization of the mouse egg’s sperm receptor bound to sperm. J Cell Biol 102: 1363–1371CrossRefGoogle Scholar
  7. Bleil JD, Wassarman PM (1988) Galactose at the non-reducing 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 85: 6778–6782PubMedCrossRefGoogle Scholar
  8. Bleil JD, Wassarman PM (1990) Identification of a ZP3-binding protein on acrosome-intact mouse sperm by photoaffinity crosslinking. Proc Natl Acad Sci USA 87: 5563–5567PubMedCrossRefGoogle Scholar
  9. Bleil JD, Greve JM, Wassarman PM (1988) Identification of a secondary sperm receptor in the mouse egg zona pellucida: role in maintenance of binding of acrosome-reacted sperm to eggs. Dev Biol 128: 376–385PubMedCrossRefGoogle Scholar
  10. Bradley MP, Garbers DL (1983) The stimulation of bovine caudal epididymal sperm forward motility by bovine cumulus-egg complexes in vitro. Biochem Biophys Res Commun 115: 777–787PubMedCrossRefGoogle Scholar
  11. Bronson R, Hamada Y (1977) Gamete interactions in vitro. Fertil Steril 28: 570–576PubMedGoogle Scholar
  12. Chamberlin ME, Dean J (1990) Human homolog of the mouse sperm receptor. Proc Natl Acad Sci USA 87: 6014–6018PubMedCrossRefGoogle Scholar
  13. Cummins JM, Yanagimachi R (1982) Sperm-egg ratios and the site of the acrosome reaction during in vivo fertilization in the hamster. Gamete Res 5: 239–256CrossRefGoogle Scholar
  14. Devreotes PN, Zigmond SH (1986) Chemotaxis in eukaryotic cells: a focus on leukocytes and Dictyostelium. Annu Rev Cell Biol 4: 649–686CrossRefGoogle Scholar
  15. Dohlman HG, Thorner J, Caron MG, Lefkowitz RJ (1991) Model systems for the study of seven-transmembrane-segment receptors. Annu Rev Biochem 60: 653–688PubMedCrossRefGoogle Scholar
  16. Dunbar BS, Prasad SV, Timmons TM (1991) Comparative structure and function of mammalian zonae pellucidae. In: Dunbar BS, O’Rand MG (eds) A comparative overview of mammalian fertilization. Plenum, New York, pp 7–114CrossRefGoogle Scholar
  17. Eisenbach M, Ralt D (1992) Precontact mammalian sperm-egg communication and role in fertilization. Am J Physiol 262 (Cell Physiol 31): C1095 - C1101PubMedGoogle Scholar
  18. Endo Y, Lee MA, Kopf GS (1987) Evidence for the role of a guanine nucleotide-binding regulatory protein in the zona pellucida-induced mouse sperm acrosome reaction. Dev Biol 119: 210–216PubMedCrossRefGoogle Scholar
  19. Endo Y, Lee MA, Kopf GS (1988) Characterization of an islet activating protein-sensitive site in mouse sperm that is involved in the zona pellucida induced acrosome reaction. Dev Biol 129: 12–24PubMedCrossRefGoogle Scholar
  20. Flechon JE, Hunter RHF (1981) Distribution of spermatozoa in the utero-tubal junction and isthmus of pigs, and their relationship with the luminal epithelium after mating: a scanning electron microscope study. Tissue Cell 13: 127–139PubMedCrossRefGoogle Scholar
  21. Florman HM, Babcock DF (1990) Progress towards understanding the molecular basis of capacitation. In: Wassarman PM (ed) Elements of mammalian fertilization I. Basic concepts. CRC uniscience series. CRC Press, Boca Raton, pp 105–132Google Scholar
  22. Florman HM, Wassarman PM (1985) 0-linked oligosaccharides of mouse egg ZP3 account for its sperm receptor activity. Cell 41: 313–324Google Scholar
  23. Florman HM, Bechtol KB, Wassarman PM (1984) Enzymatic digestion of the functions of the mouse egg’s receptor for sperm. Dev Biol 106: 243–255PubMedCrossRefGoogle Scholar
  24. Florman HM, Tombes RM, First NL, Babcock DF (1989) An adhesion-associated agonist from the zona pellucida activates G protein-promoted elevations of internal Cat+ and pH that mediate mammalian sperm acrosomal exocytosis. Dev Biol 135: 133–146PubMedCrossRefGoogle Scholar
  25. Florman, HM, Con-on ME, Kim TD, Babcock DF (1992) Activation of voltage-dependent calcium channels of mammalian sperm is required for zona pellucida-induced acrosomal exocytosis. Dev Biol 152: 304–314Google Scholar
  26. Garty NB, Galiani D, Aharonheim A, Ho YK, Phillips DM, Dekel N, Salomon Y (1988) G-proteins in mammalian gametes: an immunocytochemical study. J Cell Sci 91: 21–31PubMedGoogle Scholar
  27. Glassner M, Jones J, Kligman I, Woolkalis MJ, Gerton GL, Kopf GS (1991) Immunocytochemical and biochemical characterization of guanine nucleotide-binding regulatory proteins in mammalian spermatozoa. Dev Biol 146: 438–450PubMedCrossRefGoogle Scholar
  28. Gnessi L, Ruff MR, Fraioli F, Pert CB (1985) Demonstration of receptor-mediated chemotaxis by human spermatozoa: a novel quantitative bioassay. Exp Cell Res 161: 219–230PubMedCrossRefGoogle Scholar
  29. Godfrey EW, Dietz ME, Morstad AL, Wallskog PA, Yorde DE (1988) Acetylcholine receptor-aggregating proteins are associated with the extracellular matrix of many tissues in Torpedo. J Cell Biol 106: 1263–1272PubMedCrossRefGoogle Scholar
  30. Harper MJK (1973) Stimulation of sperm movement from the isthmus to the site of fertilization in the rabbit oviduct. Biol Reprod 8: 369–377PubMedGoogle Scholar
  31. Huang CL, Ives HE (1989) Guanosine 5’-0-(3-thiotriphosphate) potentiates both thrombin-and platelet derived growth factor-induced inositol phosphate release in permeabilized vascular smooth muscle cells. J Biol Chem 264: 4391–4397PubMedGoogle Scholar
  32. Hunter RHF, Nichol R (1983) Transport of spermatozoa in the sheep oviduct: preovulatory sequestering of cells in the caudal isthmus. J Exp ‘tool 228: 121–128Google Scholar
  33. Hunter RHF, Nichol R (1986) A preovulatory temperature gradient between the isthmus and ampulla of pig oviducts during the phase of sperm storage. J Reprod Fertil 77: 599–606PubMedCrossRefGoogle Scholar
  34. Hunter RHF, Wilmut I (1984) Sperm transport in the cow: periovulatory redistribution of viable cells within the oviduct. Reprod Nutr Dev 24: 597–608PubMedCrossRefGoogle Scholar
  35. Imamura K, Kufe D (1988) Colony stimulating factor I -induced Na+ flux into human monocytes involves activation of a pertussis toxin-sensitive GTP binding protein. J Biol Chem 263: 14093–14098PubMedGoogle Scholar
  36. Iqbal M, Shivaji S, Vijayasarathy S, Balaram P (1980) Synthetic peptides as chemoattractants for bull spermatozoa structure activity correlations. Biochem Biophys Res Commun 96: 235–242PubMedCrossRefGoogle Scholar
  37. Kalab P, Visconti P, Leclerc P, Kopf GS (1994) p95, the major phosphotyrosine-containing protein in mouse spermatozoa, is a form of hexokinase with unique properties. J Biol Chem (in press)Google Scholar
  38. Karnik NS, Newman S, Kopf GS, Gerton GL (1992) Developmental expression of G protein subunits in mouse spermatogenic cells: evidence that Gai is associated with the developing acrosome. Dev Biol 152: 393–402PubMedCrossRefGoogle Scholar
  39. Kinloch RA, Ruiz-Seiler B, Wassarman PM (1990) Genomic organization and polypeptide primary structure of zona pellucida glycoprotein hZP3, the hamster sperm receptor. Dev Biol 142: 414–421PubMedCrossRefGoogle Scholar
  40. Kligman I, Glassner M, Storey BT, Kopf GS (1991) Zona pellucida-mediated acrosomal exocytosis in mouse spermatozoa: characterization of an intermediate stage prior to the completion of the acrosome reaction. Dev Biol 145: 344–355PubMedCrossRefGoogle Scholar
  41. Kopf GS, Gerton GL (1990) The mammalian sperm acrosome and the acrosome reaction. In: Wassarman PM (ed) Elements of mammalian fertilization I: basic concepts. CRC Press, Boca Raton, pp 153–203 (CRC uniscience series)Google Scholar
  42. Kopf GS, Woolkalis MJ, Gerton GL (1986) Evidence for a guanine nucleotide-binding regulatory protein in invertebrate and mammalian sperm: identification by islet-activating protein-catalyzed ADP-ribosylation and immunochemical methods. J Biol Chem 261: 7327–7331PubMedGoogle Scholar
  43. Kopf GS, Endo Y, Mattei P, Kurasawa S, Schultz RM (1989) Egg-induced modifications of the murine zona pellucida. In: Nuccitelli RL, Clark WH, Chen- GN (eds) Mechanisms of egg activation. Plenum, New York, pp 249–272Google Scholar
  44. Leclerc P, Kopf GS (1993) Regulation of mouse sperm adenylyl cyclase by solubilized zonae pellucidae and guanine nucleotides. Biol Reprod 48 [Suppl 11: 105Google Scholar
  45. Lee MA, Storey BT (1985) Evidence for plasma membrane impermeability to small ions in acrosome-intact mouse spermatozoa bound to mouse zonae pellucidae, using an aminoacridine fluorescent probe: time course of the zona-induced acrosome reaction monitored by both chlortetracycline and pH probe fluorescence. Biol Reprod 33: 235–246PubMedCrossRefGoogle Scholar
  46. Lee MA, Storey BT (1989) Endpoint of first stage of zona pellucida-induced acrosome reaction in mouse spermatozoa characterized by acrosomal H+ and Cat+ permeability: population and single cell kinetics. Gamete Res 24: 303–326PubMedCrossRefGoogle Scholar
  47. Lee MA, Kopf GS, Storey BT (1987) Effects of phorbol esters and a diacylglycerol on the mouse sperm acrosome reaction induced by the zona pellucida. Biol Reprod 36: 617–627PubMedCrossRefGoogle Scholar
  48. Lee MA, Check JH, Kopf GS (1992) A guanine nucleotide-binding regulatory protein in human sperm mediates acrosomal exocytosis induced by the human zona pellucida. Mol Reprod Dev 31: 78–86PubMedCrossRefGoogle Scholar
  49. Leyton L, Saling PM (1989a) 95 kD sperm proteins bind ZP3 and serve as ty- rosine kinase substrates in response to zona binding. Cell 57: 123–130Google Scholar
  50. Leyton L, Sating P (1989b) Evidence that aggregation of mouse sperm recep- tors by ZP3 triggers the acrosome reaction. J Cell Biol 108: 2163–2168PubMedCrossRefGoogle Scholar
  51. Leyton L, LeGuen P, Bunch D, Saling PM (1992) Regulation of mouse gamete interaction by a sperm tyrosine kinase. Proc Natl Acad Sci USA 89: 11692–11695PubMedCrossRefGoogle Scholar
  52. Liang M, Garrison JC (1991) The epidermal growth factor receptor is coupled to a pertussis toxin-sensitive guanine nucleotide regulatory protein in rat hepatocytes. J Biol Chem 266: 13342–13349PubMedGoogle Scholar
  53. Lopez LC, Bayna EM, Litoff D, Shaper NL, Shaper JH, Shur BD (198.5) Receptor function of mouse sperm surface galactosyltransferase during fertilization. J Cell Biol 101: 1501–1510Google Scholar
  54. Luttrell L, Kilgour E, Lamer J, Romero G (1990) A pertussis toxin-sensitive G protein mediates some aspects of insulin action in BC3H-1 murine myocytes. J Biol Chem 265: 16873–16879PubMedGoogle Scholar
  55. Meyerhof W, Muller-Brechlin R, Richter D (1991) Molecular cloning of a novel putative G protein-coupled receptor expressed during rat spermiogenesis. FEBS Lett 284: 155–160PubMedCrossRefGoogle Scholar
  56. Miller DJ, Macek MB, Shur BD (1992) Complementarity between sperm surface 13–1,4-galactosyltransferase and egg-coat ZP3 mediates sperm-egg binding. Nature 357: 589–593PubMedCrossRefGoogle Scholar
  57. Miller RL (1982) Synthetic peptides are not chemoattractants for bull sperm. Gamete Res 5: 395–401CrossRefGoogle Scholar
  58. Miller RL (1985) Sperm chemo-orientation in the metazoa. In: Metz CB, Monroy A (eds) Biology of fertilization, vol 2. Biology of the sperm. Academic, New York, pp 275–337Google Scholar
  59. Moller CC, Wassarman PM (1989) Characterization of a proteinase that cleaves zona pellucida glycoprotein ZP2 following activation of mouse eggs. Dev Biol 132: 103–112PubMedCrossRefGoogle Scholar
  60. Moller CC, Bleil JD, Kinloch RA, Wassarman PM (1990) Structural and functional relationships between mouse and hamster zona pellucida glycoproteins. Dev Biol 137: 276–286PubMedCrossRefGoogle Scholar
  61. Mortillo S, Wassarman PM (1991) Differential binding of gold-labeled zona pellucida glycoproteins mZP2 and mZP3 to mouse sperm membrane compartments. Development 113: 141–149PubMedGoogle Scholar
  62. Noland TD, Garbers DL, Kopf GS (1988) An elevation in cyclic AMP concentration precedes the zona pellucida-induced acrosome reaction of mouse spermatozoa. Biol Reprod 38 [Suppl]: 94Google Scholar
  63. Overstreet JW, Cooper GW (1979) Effect of ovulation and sperm motility on the migration of rabbit spermatozoa to the site of fertilization. J Reprod Fertil 55: 53–59PubMedCrossRefGoogle Scholar
  64. Parmentier M, Libert F, Schurmans S, Schiffman S, Lefort A, Eggerickx D, Ledent C, Mollereau C, Gerard C, Perret J, Grootegoed A, Vassart G (1992) Expression of members of the putative olfactory receptor gene family in mammalian germ cells. Nature 355: 453–455PubMedCrossRefGoogle Scholar
  65. Ralt D, Goldenberg M, Fetterolf P, Thompson D, Dor J, Mashiach S, Garbers DL, Eisenbach M (1991) Sperm attraction to a follicular factor(s) correlates with human egg fertilizability. Proc Natl Acad Sci USA 88: 2840–2844PubMedCrossRefGoogle Scholar
  66. Ringuette MJ, Sobieski DA, Chamow SM, Dean J (1986) Oocyte-specific gene expression: molecular characterization of a cDNA encoding for ZP3, the sperm receptor of the mouse zona pellucida. Proc Natl Acad Sci USA 83: 4341–4345PubMedCrossRefGoogle Scholar
  67. Ringuette MJ, Chamberlin ME, Baur AW, Sobieski DA, Dean J (1988) Molecular analysis of cDNA coding for ZP3, a sperm binding protein of the mouse zona pellucida. Dev Biol 127: 287–295PubMedCrossRefGoogle Scholar
  68. Rosiere TK, Wassarman PM (1992) Identification of a region of mouse zona pellucida glycoprotein mZP3 that possesses sperm receptor activity. Dev Biol 154: 309–317PubMedCrossRefGoogle Scholar
  69. Sating PM, Sowinski J, Storey BT (1979) An ultrastructural study of epididymal mouse spermatozoa binding to zonae pellucidae in vitro: sequential relationship to the acrosome reaction. J Exp Zool 209: 229–238CrossRefGoogle Scholar
  70. Shimizu S, Tsuji M, Dean J (1983) In vitro biosynthesis of three sulfated glycoproteins of murine zonae pellucidae by oocytes grown in follicle culture. J Biol Chem 258: 5858–5863PubMedGoogle Scholar
  71. Shur BD, Hall NG (1982) A role for mouse sperm surface galactosyltransfera- se in sperm binding to the egg zona pellucida. J Cell Biol 95: 574–579PubMedCrossRefGoogle Scholar
  72. Storey BT, Kopf GS (1991) Fertilization in the mouse II. Spermatozoa. In: Dunbar BS, O’Rand MG (eds) A comparative overview of mammalian fertilization. Plenum, New York, pp 167–216CrossRefGoogle Scholar
  73. Storey BT, Hourani CL, Kim JB (1992) A transient rise in intracellular Cat+ is a precursor reaction to the zona pellucida-induced acrosome reaction in mouse sperm and is blocked by the induced acrosome reaction inhibitor, 3quinuclidinyl benzilate. Mol Reprod Dev 32: 41–50PubMedCrossRefGoogle Scholar
  74. Tesarik J, Carreras A, Mendoza C (1992) Differential sensitivity of progesterone-and zona pellucida-induced acrosome reactions to pertussis toxin. Mol Reprod Dev 34: 183–189CrossRefGoogle Scholar
  75. Vazquez MH, Phillips DM, Wassarman PM (1989) Interaction of mouse sperm with purified sperm receptors covalently linked to silica beads. J Cell Sci 92: 713–722PubMedGoogle Scholar
  76. Villanueva-Diaz C, Vadillo-Ortega F, Kably-Ambe A, Diaz-Perez M, Krivitzky SK (1990) Evidence that human follicular fluid contains a chemoattractant for spermatozoa. Fertil Steril 54: 1 180–1182Google Scholar
  77. Ward CR, Kopf GS (1993) Molecular events mediating sperm activation. Dev Biol 158: 1–26CrossRefGoogle Scholar
  78. Ward CR, Storey BT, Kopf GS (1992) Activation of a G1 protein in cell-free membrane preparations of mouse sperm by the zona pellucida and ZP3, components of the egg’s extracellular matrix. J Biol Chen 267: 1406114067Google Scholar
  79. Wassarman PM (1988) Zona pellucida glycoproteins. Annu Rev Biochem 57: 415–442PubMedCrossRefGoogle Scholar
  80. Wassarman PM (1990) Profile of a mammalian sperm receptor. Development 108: 1–17PubMedGoogle Scholar
  81. Wilde MW, Ward CR, Kopf GS (1992) Activation of a G protein in mouse sperm by the zona pellucida, an egg-associated extracellular matrix. Mol Reprod Dev 31: 297–306PubMedCrossRefGoogle Scholar
  82. Yang L, Baffy G, Rhee SG, Manning D, Hansen CA, Williamson JR (1991) Pertussis toxin-sensitive Gi protein involvement in epidermal growth factor-induced activation of phospholipase C-y in rat hepatocytes. J Biol Chem 266: 22451–22458PubMedGoogle Scholar
  83. Zamboni L (1972) Fertilization in the mouse. In: Moghissi KS, Hafez ESE (eds) Biology of mammalian fertilization and implantation. Thomas, Springfield, pp 213–262Google Scholar
  84. Zinaman M, Drobins EZ, Morales P, Brazil C, Keil M, Cross NL, Hanson FW, Overstreet JW (1989) The physiology of sperm recovered from human cervix: acrosomal status and response to inducers of the acrosome reaction. Biol Reprod 41: 791–797CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • G. S. Kopf
  • P. Kalab
  • P. Leclerc
  • X. P. Ning
  • D. Pan
  • P. Visconti

There are no affiliations available

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