The Therapeutic and Diagnostic Potential of Phospholipase C Zeta, Oocyte Activation, and Calcium in Treating Human Infertility

Abstract

Oocyte activation, a fundamental event during mammalian fertilisation, is initiated by concerted intracellular patterns of calcium (Ca2+) release, termed Ca2+ oscillations, predominantly driven by testis-specific phospholipase C zeta (PLCζ). Ca2+ exerts a pivotal role in not just regulating oocyte activation and driving fertilisation, but also in influencing the quality of embryogenesis. In humans, a failure of Ca2+ release, or defects in related mechanisms, have been reported to result in infertility. Furthermore, mutations in the PLCζ gene and abnormalities in sperm PLCζ protein and RNA, have been strongly associated with forms of male infertility where oocyte activation is deficient. Concurrently, specific patterns and profiles of PLCζ in human sperm have been linked to parameters of semen quality, suggesting the potential for PLCζ as a powerful target for both therapeutics and diagnostics of human fertility. However, further to PLCζ and given the strong role played by Ca2+ in fertilisation, targets down- and up-stream of this process may also present a significantly similar level of promise. Herein, we systematically summarise recent advancements and controversies in the field to update expanding clinical associations between Ca2+-release, PLCζ, oocyte activation and human fertility. We discuss how such associations may potentially underlie defective embryogenesis and recurrent implantation failure following fertility treatments, alongside potential diagnostic and therapeutic avenues presented by oocyte activation for the diagnosis and treatment of human infertility.

The mammalian sperm factor phospholipase C zeta is critical for early embryo division and pregnancy in humans and mice

“…Importantly, ideal morphokinetic parameters strongly favour embryos which arise from an ideal cell cycle progression in all blastomeres ( Milewski and Ajduk, 2017 ). Perhaps most relevant to this is that a specific range of PLCζ delivered to the oocyte can effectively elicit the required Ca 2+ oscillations and result in oocyte activation progression in mice and humans ( Cox et al , 2002 ; Saunders et al , 2002 ; Yamaguchi et al , 2017 ), which are estimated to be approximately double (20–40 fg) in mouse ( Kashir et al , 2022 ; Abdulsamad et al , 2023 ), indicating a wide range of variability of sperm PLCζ that could activate with varying efficacies of cell cycle progression.…”

“…Subsequently, correlations with embryonic morphokinetic parameters has been used as a standard practice in clinics as predictors of embryo quality, blastocyst formation and ultimately implantation, pregnancy and live birth ( Cruz et al , 2011 ; Hlinka et al , 2012 ), with specifically the second and third round of cell divisions (within an ideal range of 8–12 h) representing the most potent indicators of embryonic developmental potential in humans ( Meseguer et al , 2011 ; Desai et al , 2014 ; Kim et al , 2017 ; Milewski et al , 2018 ). Considering such potential impact of PLCζ upon embryogenesis via Ca 2+ release profiles, as well as considering the variability of PLCζ observed amongst patients ( Kashir et al , 2013 ), it is possible that PLCζ could affect such parameters of embryogenesis ( Kashir, 2020 ; Abdulsamad et al , 2023 ), and perhaps also be used to predict pregnancy rates.…”

Applications of advances in mRNA-based platforms as therapeutics and diagnostics in reproductive technologies

“…One circumstance where fertilization following ICSI appears to be severely diminished is in globozoospermia, a rare disorder affecting ~0.1% of infertile men and characterized by round-headed, acrosome-less sperm cells (Liu et al, 1995;Heindryckx et al, 2005;Dam et al, 2006;Fesahat et al, 2019). Such infertile, males also tend to exhibit mutations in the PLCζ gene (Heytens et al, 2009;Kashir et al, 2011b), with numerous such mutations now identified multiple independent studies and correlated with oocyte activation failure in humans (Abdulsamad et al, 2023;Jones et al, 2022;Kashir, 2020). Indeed, PLCζ also seems to be an important indicator of sperm health, correlating with all examined sperm parameters used within the clinic (Kashir et al, 2010;Kashir et al, 2011a;Kashir et al, 2011b;Kashir et al, 2012b;Kashir et al, 2012c;Kashir et al, 2012d;Kashir et al, 2012e;Ramadan et al, 2012;Yelumalai et al, 2012;Kashir et al, 2013a;Nomikos et al, 2013a;Kashir et al, 2013b;Kashir et al, 2014;Yelumalai et al, 2015;Kashir et al, 2016;Kashir, 2020;Kashir et al, 2020;Kashir et al, 2022b;Kashir et al, 2023).…”

Phospholipase C Zeta 1 (PLCZ1): The Function and Potential for Fertility Assessment and In Vitro Embryo Production in Cattle and Horses

“…In addition, Ca 2+ upregulates PKC, which phosphorylates myristoylated alanine-rich C kinase substrate (MARCKS), inducing actin breakdown, and allowing for cortical granule exocytosis. The inactivation of mitogen-activated protein kinase (MAPK) by Ca 2+ leads to pronuclear formation ( Figure 1 B) [ 88 , 89 ]. The initial communication between the sperm and oocyte after fertilization is still unknown.…”