Starting a new life: Sperm PLC-zeta mobilizes the Ca2+signal that induces egg activation and embryo development

Cell Signalling Laboratory, WHRI, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
BioEssays (Impact Factor: 4.73). 11/2011; 34(2):126-34. DOI: 10.1002/bies.201100127
Source: PubMed


We have discovered that a single sperm protein, phospholipase C-zeta (PLCζ), can stimulate intracellular Ca(2+) signalling in the unfertilized oocyte ('egg') culminating in the initiation of embryonic development. Upon fertilization by a spermatozoon, the earliest observed signalling event in the dormant egg is a large, transient increase in free Ca(2+) concentration. The fertilized egg responds to the intracellular Ca(2+) rise by completing meiosis. In mammalian eggs, the Ca(2+) signal is delivered as a train of long-lasting cytoplasmic Ca(2+) oscillations that begin soon after gamete fusion and persist beyond the completion of meiosis. Sperm PLCζ effects Ca(2+) release from egg intracellular stores by hydrolyzing the membrane lipid PIP(2) and consequent stimulation of the inositol 1,4,5-trisphosphate (InsP(3) ) receptor Ca(2+) -signalling pathway, leading to egg activation and early embryogenesis. Recent advances have refined our understanding of how PLCζ induces Ca(2+) oscillations in the egg and also suggest its potential dysfunction as a cause of male infertility.

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    • "Ca 2+ oscillations during mammalian oocyte activation are generated in an IP 3 -mediated manner, requiring that phosphatidylinositol 4,5- bisphosphate (PIP 2 ) is hydrolysed to liberate IP 3 and diacylglycerol. This is consistent with the idea that the sperm factor is a phospholipase C (PLC) (Nomikos et al., 2012, 2013a). Accordingly, accumulating data over the past decade has supported the identity of this sperm factor to be a novel, testis-specific PLC isozyme, termed PLCzeta (PLCz) (Cox et al., 2002; Saunders et al., 2002). "
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    ABSTRACT: Mammalian oocyte activation is mediated by cytosolic calcium (Ca2+) oscillations initiated upon delivery of a putative 'sperm factor' by the fertilizing sperm. Previous studies suggest the identity of this sperm factor as the testis-specific phospholipase C-zeta (PLCζ). Recently, a post-acrosomal sheath WW domain-binding protein (PAWP) has been proposed as an alternative sperm factor candidate, following a report that human PAWP protein and cRNA elicited Ca2+ oscillations in mouse and human oocytes. Those Ca2+ oscillations were inhibited by a PAWP-derived peptide corresponding to a functional PPGY binding motif. Herein, using a series of human PAWP expression constructs, we demonstrate that both human PAWP protein and cRNA are, in our experiments, unable to elicit Ca2+ release following microinjection into mouse oocytes. Parallel experiments performed with human PLCζ elicited the characteristic Ca2+ oscillations present at mammalian fertilization, which produced oocyte activation and embryo development. Furthermore, sperm-induced Ca2+ oscillations were not inhibited by the PAWP-derived PPGY peptide following in vitro fertilization or intracytoplasmic sperm injection. Thus, the functional disparity with PLCζ leads us to conclude that human PAWP is neither sufficient nor necessary for the Ca2+ oscillations that initiate mammalian oocyte activation at fertilization.
    Molecular Human Reproduction 06/2015; 21(9). DOI:10.1093/molehr/gav034 · 3.75 Impact Factor
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    • "In all species studied, such Ca 2+ oscillations are both necessary and sufficient for the completion of all the events of oocyte activation and early embryonic development (Nomikos et al., 2012). Ca 2+ oscillations in mammalian oocytes occur as a result of inositol trisphosphate (IP 3 )mediated Ca 2+ release from internal stores such as the endoplasmic reticulum (ER) (Miyazaki et al., 1992), with the amplitude, duration and frequency of Ca 2+ oscillations being largely species specific (Swann et al., 2006; Nomikos et al., 2012). However, the sperm factor causing the Ca 2+ oscillations is not species specific because the injection of human sperm into mouse oocytes can cause Ca 2+ oscillations as well as oocyte activation (Vanden Meerschaut et al., 2013). "
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    ABSTRACT: A sperm-specific phospholipase C-zeta (PLCζ) is believed to play an essential role in oocyte activation during mammalian fertilization. Sperm PLCζ has been shown to trigger a prolonged series of repetitive Ca2+ transients or oscillations in oocytes that precede activation. This remarkable intracellular Ca2+ signalling phenomenon is a distinctive characteristic observed during in vitro fertilization by sperm. Previous studies have notably observed an apparent differential ability of PLCζ from disparate mammalian species to trigger Ca2+ oscillations in mouse oocytes. However, the molecular basis and confirmation of the apparent PLCζ species difference in activity remains to be provided. In the present study, we provide direct evidence for the superior effectiveness of human PLCζ relative to mouse PLCζ in generating Ca2+ oscillations in mouse oocytes. In addition, we have designed and constructed a series of human/mouse PLCζ chimeras to enable study of the potential role of discrete PLCζ domains in conferring the enhanced Ca2+ signalling potency of human PLCζ. Functional analysis of these human/mouse PLCζ domain chimeras suggests a novel role of the EF-hand domain in the species-specific differences in PLCζ activity. Our empirical observations are compatible with a basic mathematical model for the Ca2+ dependence of generating cytoplasmic Ca2+ oscillations in mammalian oocytes by sperm PLCζ.
    Molecular Human Reproduction 01/2014; 20(6). DOI:10.1093/molehr/gau011 · 3.75 Impact Factor
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    • "The ID1, a DNA-binding protein inhibitor, associated with aggressive nonstandard breast cancer cells could be controlled by cannabidiol in cannabis [6]. The PLCZ1, phospholipase C Zeta 1, was reported to be delivered by the sperm to control egg activation [7]. Calibration based on 16S rRNA (human and mouse) enables a relative measure of the evolutionary pressure of the above genes between human and mouse. "
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    ABSTRACT: DNA informatics represented by Shannon entropy and fractal dimension have been used to form 2D maps of related genes in various mammals. The distance between points on these maps for corresponding mRNA sequences in different species is used to study evolution. By quantifying the similarity of genes between species, this distance might be indicated when studies on one species (mouse) would tend to be valid in the other (human). The hypothesis that a small distance from mouse to human could facilitate mouse to human translational medicine success is supported by the studied ESR-1, LMNA, Myc, and RNF4 sequences. ID1 and PLCZ1 have larger separation. The collinearity of displacement vectors is further analyzed with a regression model, and the ID1 result suggests a mouse-chimp-human translational medicine approach. Further inference was found in the tumor suppression gene, p53, with a new hypothesis of including the bovine PKM2 pathways for targeting the glycolysis preference in many types of cancerous cells, consistent with quantum metabolism models. The distance between mRNA and protein coding CDS is proposed as a measure of the pressure associated with noncoding processes. The Y-chromosome DYS14 in fetal micro chimerism that could offer protection from Alzheimer's disease is given as an example.
    03/2013; 2013:582358. DOI:10.1155/2013/582358
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