Skip to main content Accessibility help
  • Print publication year: 2017
  • Online publication date: May 2017

12 - Fundamental Role for Sperm Phospholipase C ζ in Mammalian Fertilization

1.Nomikos, M, Swann, K, Lai, FA. Starting a new life: Sperm PLC-zeta mobilizes the Ca2+ signal that induces egg activation and embryo development: An essential phospholipase C with implications for male infertility. Bioessays 2012; 34: 126–34.
2.Stricker, SA. Comparative biology of calcium signaling during fertilization and egg activation in animals. Dev Biol 1999; 211: 157–76.
3.Jones, KT. Mammalian egg activation:From Ca2+ spiking to cell cycle progression. Reproduction 2005; 130: 813–23.
4.Runft, LL, Jaffe, LA, Mehlmann, LM. Egg activation at fertilization: Where it all begins. Dev Biol 2002; 245: 237–54.
5.Nomikos, M, Kashir, J, Swann, K, Lai, FA. Sperm PLCzeta: From structure to Ca2+ oscillations, egg activation and therapeutic potential. FEBS Lett 2013; 587: 3,609–16.
6.Kline, D, Kline, JT. Repetitive calcium transients and the role of calcium in exocytosis and cell cycle activation in the mouse egg. Dev Biol 1992; 149: 8089.
7.Fissore, RA, Dobrinsky, JR, Balise, JJ, Duby, RT, Robl, JM. Patterns of intracellular Ca2+ concentrations in fertilized bovine eggs. Biol Reprod 1992; 47: 960–69.
8.Miyazaki, S, Yuzaki, M, Nakada, K, Shirakawa, H, Nakanishi, S, Nakade, S et al. Block of Ca2+ wave and Ca2+ oscillation by antibody to the inositol 1,4,5-trisphosphate receptor in fertilized hamster eggs. Science 1992; 257: 251–5.
9.Miyazaki, S, Shirakawa, H, Nakada, K, Honda, Y. Essential role of the inositol 1,4,5-trisphosphate receptor/Ca2+ release channel in Ca2+ waves and Ca2+ oscillations at fertilization of mammalian eggs. Dev Biol 1993; 158: 6278.
10.Brind, S, Swann, K, Carroll, J. Inositol 1,4,5-trisphosphate receptors are downregulated in mouse oocytes in response to sperm or adenophostin A but not to increases in intracellular Ca(2+) or egg activation. Dev Biol 2000; 223: 251–65.
11.Jellerette, T, He, CL, Wu, H, Parys, JB, Fissore, RA. Down-regulation of the inositol 1,4,5-trisphosphate receptor in mouse eggs following fertilization or parthenogenetic activation. Dev Biol 2000; 223: 238–50.
12.Wu, H, Smyth, J, Luzzi, V, Fukami, K, Takenawa, T, Black, SL et al. Sperm factor induces intracellular free calcium oscillations by stimulating the phosphoinositide pathway. Biol Reprod 2001; 64: 1,338–49.
13.Swann, K. Ca2+ oscillations and sensitization of Ca2+ release in unfertilized mouse eggs injected with a sperm factor. Cell Calcium 1994; 15: 331–9.
14.Jones, KT, Nixon, VL. Sperm-induced Ca(2+) oscillations in mouse oocytes and eggs can be mimicked by photolysis of caged inositol 1,4,5-trisphosphate: Evidence to support a continuous low level production of inositol 1, 4,5-trisphosphate during mammalian fertilization. Dev Biol 2000; 225: 112.
15.Swann, K. A cytosolic sperm factor stimulates repetitive calcium increases and mimics fertilization in hamster eggs. Development 1990; 110: 1,295302.
16.Swann, K, Larman, MG, Saunders, CM, Lai, FA. The cytosolic sperm factor that triggers Ca2+ oscillations and egg activation in mammals is a novel phospholipase C: PLCzeta. Reproduction 2004; 127: 431–9.
17.Dale, B, DeFelice, LJ, Ehrenstein, G. Injection of a soluble sperm fraction into sea-urchin eggs triggers the cortical reaction. Experientia 1985; 41: 1,068–70.
18.Stricker, SA. Intracellular injections of a soluble sperm factor trigger calcium oscillations and meiotic maturation in unfertilized oocytes of a marine worm. Dev Biol 1997; 186: 185201.
19.Tesarik, J, Sousa, M, Testart, J. Human oocyte activation after intracytoplasmic sperm injection. Hum Reprod 1994; 9: 511–8.
20.Nakano, Y, Shirakawa, H, Mitsuhashi, N, Kuwabara, Y, Miyazaki, S. Spatiotemporal dynamics of intracellular calcium in the mouse egg injected with a spermatozoon. Mol Hum Reprod 1997; 3: 1,087–93.
21.Rice, A, Parrington, J, Jones, KT, Swann, K. Mammalian sperm contain a Ca(2+)-sensitive phospholipase C activity that can generate InsP(3) from PIP(2) associated with intracellular organelles. Dev Biol 2000; 228: 125–35.
22.Mehlmann, LM, Chattopadhyay, A, Carpenter, G, Jaffe, LA. Evidence that phospholipase C from the sperm is not responsible for initiating Ca(2+) release at fertilization in mouse eggs. Dev Biol 2001; 236: 492501.
23.Parrington, J, Jones, ML, Tunwell, R, Devader, C, Katan, M, Swann, K. Phospholipase C isoforms in mammalian spermatozoa: Potential components of the sperm factor that causes Ca2+ release in eggs. Reproduction 2002; 123: 31–9.
24.Saunders, CM, Larman, MG, Parrington, J, Cox, LJ, Royse, J, Blayney, LM et al. PLC zeta: a sperm-specific trigger of Ca(2+) oscillations in eggs and embryo development. Development 2002; 129: 3,533–44.
25.Cox, LJ, Larman, MG, Saunders, CM, Hashimoto, K, Swann, K, Lai, FA. Sperm phospholipase Czeta from humans and cynomolgus monkeys triggers Ca2+ oscillations, activation and development of mouse oocytes. Reproduction 2002; 124: 611–23.
26.Kouchi, Z, Fukami, K, Shikano, T, Oda, S, Nakamura, Y, Takenawa, T et al. Recombinant phospholipase Czeta has high Ca2+ sensitivity and induces Ca2+ oscillations in mouse eggs. J Biol Chem 2004; 279: 10,408–12.
27.Nomikos, M, Yu, Y, Elgmati, K, Theodoridou, M, Campbell, K, Vassilakopoulou, V et al. Phospholipase Czeta rescues failed oocyte activation in a prototype of male factor infertility. Fertil Steril 2013; 99: 7685.
28.Yu, Y, Saunders, CM, Lai, FA, Swann, K. Preimplantation development of mouse oocytes activated by different levels of human phospholipase C zeta. Hum Reprod 2008; 23: 365–73.
29.Nomikos, M, Blayney, LM, Larman, MG, Campbell, K, Rossbach, A, Saunders, CM et al. Role of phospholipase C-zeta domains in Ca2+-dependent phosphati-dylinositol 4,5-bisphosphate hydrolysis and cytoplasmic Ca2+ oscillations. J Biol Chem 2005; 280: 31,011–8.
30.Knott, JG, Kurokawa, M, Fissore, RA, Schultz, RM, Williams, CJ. Transgenic RNA interference reveals role for mouse sperm phospholipase Czeta in triggering Ca2+ oscillations during fertilization. Biol Reprod 2005; 72: 992–6.
31.Yoon, SY, Jellerette, T, Salicioni, AM, Lee, HC, Yoo, MS, Coward, K et al. Human sperm devoid of PLC, zeta 1 fail to induce Ca(2+) release and are unable to initiate the first step of embryo development. J Clin Invest 2008; 118: 3,671–81.
32.Heytens, E, Parrington, J, Coward, K, Young, C, Lambrecht, S, Yoon, SY et al. Reduced amounts and abnormal forms of phospholipase C zeta (PLCzeta) in spermatozoa from infertile men. Hum Reprod 2009; 24: 2,417–28.
33.Kashir, J, Konstantinidis, M, Jones, C, Lemmon, B, Lee, HC, Hamer, R et al. A maternally inherited autosomal point mutation in human phospholipase C zeta (PLCzeta) leads to male infertility. Hum Reprod 2012; 27: 222–31.
34.Nomikos, M, Elgmati, K, Theodoridou, M, Calver, BL, Cumbes, B, Nounesis, G et al. Male infertility-linked point mutation disrupts the Ca2+ oscillation-inducing and PIP(2) hydrolysis activity of sperm PLCzeta. Biochem J 2011; 434: 211–7.
35.Kashir, J, Heindryckx, B, Jones, C, De Sutter, P, Parrington, J, Coward, K. Oocyte activation, phospholipase C zeta and human infertility. Hum Reprod Update 2010; 16: 690703.
36.Parrington, J, Swann, K, Shevchenko, VI, Sesay, AK, Lai, FA. Calcium oscillations in mammalian eggs triggered by a soluble sperm protein. Nature 1996; 379: 364–8.
37.Sette, C, Bevilacqua, A, Bianchini, A, Mangia, F, Geremia, R, Rossi, P. Parthenogenetic activation of mouse eggs by microinjection of a truncated c-kit tyrosine kinase present in spermatozoa. Development 1997; 124: 2,267–74.
38.Swann, K, Lai, FA. PLCzeta and the initiation of Ca(2+) oscillations in fertilizing mammalian eggs. Cell Calcium 2013; 53: 5562.
39.Nomikos, M. Novel signalling mechanism and clinical applications of sperm-specific PLCzeta. Biochem Soc Trans 2015; 43: 371–6.
40.Aarabi, M, Balakier, H, Bashar, S, Moskovtsev, SI, Sutovsky, P, Librach, CL et al. Sperm-derived WW domain-binding protein, PAWP, elicits calcium oscillations and oocyte activation in humans and mice. FASEB J 2014; 28: 4,434–40.
41.Wu, AT, Sutovsky, P, Manandhar, G, Xu, W, Katayama, M, Day, BN et al. PAWP, a sperm-specific WW domain-binding protein, promotes meiotic resumption and pronuclear development during fertilization. J Biol Chem 2007; 282: 12,164–75.
42.Nomikos, M, Sanders, JR, Theodoridou, M, Kashir, J, Matthews, E, Nounesis, G et al. Sperm-specific post-acrosomal WW-domain binding protein (PAWP) does not cause Ca2+ release in mouse oocytes. Mol Hum Reprod 2014; 20: 938–47.
43.Nomikos, M, Sanders, JR, Kashir, J, Sanusi, R, Buntwal, L, Love, D et al. Functional disparity between human PAWP and PLCzeta in the generation of Ca2+ oscillations for oocyte activation. Mol Hum Reprod 2015; 21: 702–10.
44.Satouh, Y, Nozawa, K, Ikawa, M. Sperm postacrosomal WW domain-binding protein is not required for mouse egg activation. Biol Reprod 2015; 93: 94.
45.Rebecchi, MJ, Pentyala, SN. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol Rev 2000; 80: 1,291133.
46.Lomasney, JW, Cheng, HF, Wang, LP, Kuan, Y, Liu, S, Fesik, SW et al. Phosphatidylinositol 4,5-bisphosphate binding to the pleckstrin homology domain of phospholipase C-delta1 enhances enzyme activity. J Biol Chem 1996; 271: 25,316–26.
47.Pawelczyk, T, Lowenstein, JM. Binding of phospholipase C delta 1 to phospholipid vesicles. Biochem J 1993; 291 (Pt 3): 693–6.
48.Suh, PG, Park, JI, Manzoli, L, Cocco, L, Peak, JC, Katan, M et al. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep 2008; 41: 415–34.
49.Theodoridou, M, Nomikos, M, Parthimos, D, Gonzalez-Garcia, JR, Elgmati, K, Calver, BL et al. Chimeras of sperm PLCzeta reveal disparate protein domain functions in the generation of intracellular Ca2+ oscillations in mammalian eggs at fertilization. Mol Hum Reprod 2013; 19: 852–64.
50.Kashir, J, Nomikos, M, Lai, FA, Swann, K. Sperm-induced Ca2+ release during egg activation in mammals. Biochem Biophys Res Commun 2014; 450: 1,204–11.
51.Hicks, SN, Jezyk, MR, Gershburg, S, Seifert, JP, Harden, TK, Sondek, J. General and versatile autoinhibition of PLC isozymes. Mol Cell 2008; 31: 383–94.
52.Gresset, A, Hicks, SN, Harden, TK, Sondek, J. Mechanism of phosphorylation-induced activation of phospholipase C-gamma isozymes. J Biol Chem 2010; 285: 35,836–47.
53.Nomikos, M, Elgmati, K, Theodoridou, M, Georgilis, A, Gonzalez-Garcia, JR, Nounesis, G et al. Novel regulation of PLCzeta activity via its XY-linker. Biochem J 2011; 438: 427–32.
54.Nomikos, M, Mulgrew-Nesbitt, A, Pallavi, P, Mihalyne, G, Zaitseva, I, Swann, K et al. Binding of phosphoinositide-specific phospholipase C-zeta (PLC-zeta) to phospholipid membranes: Potential role of an unstructured cluster of basic residues. J Biol Chem 2007; 282: 16,644–53.
55.Nomikos, M, Elgmati, K, Theodoridou, M, Calver, BL, Nounesis, G, Swann, K et al. Phospholipase Czeta binding to PtdIns(4,5)P2 requires the XY-linker region. J Cell Sci 2011; 124: 2,582–90.
56.Larman, MG, Saunders, CM, Carroll, J, Lai, FA, Swann, K. Cell cycle-dependent Ca2+ oscillations in mouse embryos are regulated by nuclear targeting of PLCzeta. J Cell Sci 2004; 117: 2,513–21.
57.Yoda, A, Oda, S, Shikano, T, Kouchi, Z, Awaji, T, Shirakawa, H et al. Ca2+ oscillation-inducing phospholipase C zeta expressed in mouse eggs is accumulated to the pronucleus during egg activation. Dev Biol 2004; 268: 245–57.
58.Ito, M, Shikano, T, Kuroda, K, Miyazaki, S. Relationship between nuclear sequestration of PLCzeta and termination of PLCzeta-induced Ca2+ oscillations in mouse eggs. Cell Calcium 2008; 44: 400–10.
59.Ito, M, Shikano, T, Oda, S, Horiguchi, T, Tanimoto, S, Awaji, T et al. Difference in Ca2+ oscillation-inducing activity and nuclear translocation ability of PLCZ1, an egg-activating sperm factor candidate, between mouse, rat, human, and medaka fish. Biol Reprod 2008; 78: 1,081–90.
60.Kurokawa, M, Yoon, SY, Alfandari, D, Fukami, K, Sato, K, Fissore, RA. Proteolytic processing of phospholipase Czeta and [Ca2+]i oscillations during mammalian fertilization. Dev Biol 2007; 312: 407–18.
61.Swann, K, Saunders, CM, Rogers, NT, Lai, FA. PLCzeta(zeta): A sperm protein that triggers Ca2+ oscillations and egg activation in mammals. Semin Cell Dev Biol 2006; 17: 264–73.
62.Nomikos, M, Theodoridou, M, Elgmati, K, Parthimos, D, Calver, BL, Buntwal, L et al. Human PLCzeta exhibits superior fertilization potency over mouse PLCzeta in triggering the Ca(2+) oscillations required for mammalian oocyte activation. Mol Hum Reprod 2014; 20: 489–98.
63.Kouchi, Z, Shikano, T, Nakamura, Y, Shirakawa, H, Fukami, K, Miyazaki, S. The role of EF-hand domains and C2 domain in regulation of enzymatic activity of phospholipase Czeta. J Biol Chem 2005; 280: 21,015–21.
64.Nomikos, M, Sanders, JR, Parthimos, D, Buntwal, L, Calver, BL, Stamatiadis, P et al. Essential role of the EF-hand domain in targeting sperm phospholipase Czeta to membrane PIP2. J Biol Chem 2015; 290: 29,519–30.
65.Nalefski, EA, Falke, JJ. The C2 domain calcium-binding motif: Structural and functional diversity. Protein Sci 1996; 5: 2,375–90.
66.Lomasney, JW, Cheng, HF, Roffler, SR, King, K. Activation of phospholipase C delta1 through C2 domain by a Ca(2+)-enzyme-phosphatidylserine ternary complex. J Biol Chem 1999; 274: 21,995–2,001.
67.Fujimoto, S, Yoshida, N, Fukui, T, Amanai, M, Isobe, T, Itagaki, C et al. Mammalian phospholipase Czeta induces oocyte activation from the sperm perinuclear matrix. Dev Biol 2004; 274: 370–83.
68.Young, C, Grasa, P, Coward, K, Davis, LC, Parrington, J. Phospholipase C zeta undergoes dynamic changes in its pattern of localization in sperm during capacitation and the acrosome reaction. Fertil Steril 2009; 91: 2,230–42.
69.Kaewmala, K, Uddin, MJ, Cinar, MU, Grosse-Brinkhaus, C, Jonas, E, Tesfaye, D et al. Investigation into association and expression of PLCz and COX-2 as candidate genes for boar sperm quality and fertility. Reprod Domest Anim 2012; 47: 213–23.
70.Bedford-Guaus, SJ, McPartlin, LA, Xie, J, Westmiller, SL, Buffone, MG, Roberson, MS. Molecular cloning and characterization of phospholipase C zeta in equine sperm and testis reveals species-specific differences in expression of catalytically active protein. Biol Reprod 2011; 85: 7888.
71.Aarabi, M, Yu, Y, Xu, W, Tse, MY, Pang, SC, Yi, YJ et al. The testicular and epididymal expression profile of PLCzeta in mouse and human does not support its role as a sperm-borne oocyte activating factor. PLoS One 2012; 7: e33496.
72.Yu, Y, Nomikos, M, Theodoridou, M, Nounesis, G, Lai, FA, Swann, K. PLCzeta causes Ca(2+) oscillations in mouse eggs by targeting intracellular and not plasma membrane PI(4,5)P(2). Mol Biol Cell 2012; 23: 371–80.
73.Halet, G, Tunwell, R, Balla, T, Swann, K, Carroll, J. The dynamics of plasma membrane PtdIns(4,5)P(2) at fertilization of mouse eggs. J Cell Sci 2002; 115: 2,139–49.
74.Yu, Y, Halet, G, Lai, FA, Swann, K. Regulation of diacylglycerol production and protein kinase C stimulation during sperm- and PLCzeta-mediated mouse egg activation. Biol Cell 2008; 100: 633–43.
75.Phillips, SV, Yu, Y, Rossbach, A, Nomikos, M, Vassilakopoulou, V, Livaniou, E et al. Divergent effect of mammalian PLCzeta in generating Ca2+ oscillations in somatic cells compared with eggs. Biochem J 2011; 438: 545–53.
76.Ross, PJ, Beyhan, Z, Iager, AE, Yoon, SY, Malcuit, C, Schellander, K et al. Parthenogenetic activation of bovine oocytes using bovine and murine phospholipase C zeta. BMC Dev Biol 2008; 8: 16.
77.Saunders, CM, Swann, K, Lai, FA. PLCzeta, a sperm-specific PLC and its potential role in fertilization. Biochem Soc Symp 2007: 2336.
78.Cooney, MA, Malcuit, C, Cheon, B, Holland, MK, Fissore, RA, D'Cruz, NT. Species-specific differences in the activity and nuclear localization of murine and bovine phospholipase C zeta 1. Biol Reprod 2010; 83: 92101.
79.Kurokawa, M, Sato, K, Wu, H, He, C, Malcuit, C, Black, SJ et al. Functional, biochemical, and chromatographic characterization of the complete [Ca2+]i oscillation-inducing activity of porcine sperm. Dev Biol 2005; 285: 376–92.
80.Lawrence, Y, Whitaker, M, Swann, K. Sperm–egg fusion is the prelude to the initial Ca2+ increase at fertilization in the mouse. Development 1997; 124: 233–41.
81.Boivin, J, Bunting, L, Collins, JA, Nygren, KG. International estimates of infertility prevalence and treatment-seeking: Potential need and demand for infertility medical care. Hum Reprod 2007; 22: 1,506–12.
82.Ramadan, WM, Kashir, J, Jones, C, Coward, K. Oocyte activation and phospholipase C zeta (PLCzeta): diagnostic and therapeutic implications for assisted reproductive technology. Cell Commun Signal 2012; 10: 12.
83.Javed, M, Esfandiari, N, Casper, RF. Failed fertilization after clinical intracytoplasmic sperm injection. Reprod Biomed Online 2010; 20: 5667.
84.Vanden Meerschaut, F, Leybaert, L, Nikiforaki, D, Qian, C, Heindryckx, B, De Sutter, P. Diagnostic and prognostic value of calcium oscillatory pattern analysis for patients with ICSI fertilization failure. Hum Reprod 2013; 28: 8798.
85.Neri, QV, Lee, B, Rosenwaks, Z, Machaca, K, Palermo, GD. Understanding fertilization through intracytoplasmic sperm injection (ICSI). Cell Calcium 2014; 55: 2437.
86.Escoffier, J, Lee, HC, Yassine, S, Zouari, R, Martinez, G, Karaouzène, T et al. Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP. Hum Mol Genet 2016 doi: 10.1093/hmg/ddv617.
87.Sanusi, R, Yu, Y, Nomikos, M, Lai, FA, Swann, K. Rescue of failed oocyte activation after ICSI in a mouse model of male factor infertility by recombinant phospholipase Czeta. Mol Hum Reprod 2015; 21: 783–91.
88.Grasa, P, Coward, K, Young, C, Parrington, J. The pattern of localization of the putative oocyte activation factor, phospholipase Czeta, in uncapacitated, capacitated, and ionophore-treated human spermatozoa. Hum Reprod 2008; 23: 2,513–22.
89.Yelumalai, S, Yeste, M, Jones, C, Amdani, SN, Kashir, J, Mounce, G et al. Total levels, localization patterns, and proportions of sperm exhibiting phospholipase C zeta are significantly correlated with fertilization rates after intracytoplasmic sperm injection. Fertil Steril 2015; 104: 561–8 e4.