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PLCζ: or PAWP: revisiting the putative mammalian sperm factor that triggers egg activation and embryogenesis
Recent data have emerged suggesting the sperm factor may be a post-acrosomal sheath WW domain-binding protein (PAWP). However, a significant body of research points to a testis-specific phospholipase C zeta (PLCζ:) as the sperm factor. Herein, we examine the evidence presented in favour of PAWP in relation to PLCζ: and the requisite physiological properties of the mammalian sperm factor.
187. Resolving egg activation at fertilization [Forum/Discussion]
from: Administrator (office@fertaid.com), Australia on 6/07/2015 8:07:44 AM Profession:
Comment: In mammals, egg activation involves a series of calcium concentration changes (or ‘oscillations’). These oscillations are considered to be caused by a ‘sperm-specific protein factor’.
Resolving egg activation at fertilization: ‘Oh sperm factor! Wherefore art thou?’
Junaid Kashir, Michail Nomikos, Karl Swann & F. Anthony Lai*, Cardiff University School of Medicine, Cardiff, UK
*Email: LaiT@cf.ac.uk
The fundamental event during creation of a new human is when the male’s fertilising sperm initiates embryo development by ‘activating’ the female egg. In mammals, egg activation involves a series of calcium concentration changes (or ‘oscillations’). These oscillations are considered to be caused by a ‘sperm-specific protein factor’ that is delivered to the egg following sperm/egg fusion at fertilisation.
Of the various candidates proposed as the sperm factor thus far, a wide variety of data reported by multiple independent laboratories worldwide have cumulatively been consistent with the proposition that the sperm factor’s identity is a unique phospholipase C (PLC) enzyme, found exclusively within sperm and testes, termed PLC-zeta (PLCz). Injection of laboratory-made PLCz into mammalian eggs produces the same profile of calcium oscillations as occurs during normal fertilisation, while depletion of sperm PLCz abolishes these striking patterns of calcium release. Clinically, patient sperm that repeatedly fails to successfully activate eggs after in vitro fertilisation (IVF) or intra-cytoplasmic sperm injection (ICSI), were found to either possess abnormal forms or reduced/absent levels of PLCz.
Recently, however, studies from a single laboratory have proposed that the identity of the sperm factor is a different sperm-specific protein, termed post-acrosomal sheath WW domain-binding protein (PAWP), and that this protein represents a more suitable candidate for the sperm factor than PLCz. These PAWP studies purportedly found that laboratory-made PAWP was able to successfully cause calcium release in mammalian eggs, while blocking PAWP with an inhibitory peptide prevented fertilisation from successfully occurring. However, there remain major concerns that require addressing before PAWP becomes a serious candidate for the physiological ‘sperm factor’ (1). The main concern is that we have been unable to reproduce any of the original findings claiming that PAWP can cause calcium oscillations in mouse eggs. We are also unable to find any observable inhibitory effect on fertilization of the PAWP ‘inhibitory’ peptides (2). As far as we know, we are the only group to attempt to replicate the specific findings regarding PAWP.
Currently, no experimental evidence exists to explain the biochemical context of PAWPs mechanism of action, nor have the specific structural and functional correlates of PAWP’s properties been experimentally determined. It also remains unclear, even from the reports suggesting PAWP can produce calcium release/egg activation, whether PAWP is able to drive subsequent embryogenesis to the blastocyst stage, as has been demonstrated for PLCz.
At present, a significant body of evidence constituting the majority of research on this topic supports PLCz as the ‘sperm factor’, including analysis of the unique biochemical and structural features of this enzyme, its physiological mechanism of action within mammalian eggs at fertilisation, as well as important clinical relevance, all within the context of egg activation. The reliability of such data is strengthened by complementary PLCz research from multiple laboratories around the world who have confirmed each other’s work independently.
Unfortunately, the same reproducibility does not currently apply to PAWP, where there is no independent confirmatory data available. Thus, at least until independent, novel, and convincing contrary data becomes available in support of a precise role for PAWP in egg activation at fertilization, it would be prudent not to exclude the stronger, well-accepted candidate, PLCz.
(1) PLCz or PAWP: revisiting the putative mammalian sperm factor that triggers egg activation and embryogenesis. Junaid Kashir, Michail Nomikos, Karl Swann & F. Anthony Lai. Molecular Human Reproduction 2015(in the press) doi:10.1093/molehr/gav009 - http://www.ncbi.nlm.nih.gov/pubmed/26116451
(2) Functional disparity between human PAWP and PLCz in the generation of Ca2+ oscillations for oocyte activation. Michail Nomikos, Jessica R. Sanders, Junaid Kashir, Randa Sanusi, Luke Buntwal, Daniel Love, Peter Ashley, David Sanders, Paul Knaggs, Adnan Bunkheila, Karl Swann & F. Anthony Lai. Molecular Human Reproduction 21(5):383-8, 2015. doi:10.1093/molehr/gav034 - http://www.ncbi.nlm.nih.gov/pubmed/25722320
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