“This is where it all started” – the pivotal role of PLCζ within the sophisticated process of mammalian reproduction: a systemic review

Abstract

Mammalian reproduction is one of the most complex and fascinating biological phenomenon, which aims to transfer maternal and paternal genetic material to the next generation. At the end of oogenesis and spermatogenesis, both haploid gametes contain a single set of chromosomes ready to form the zygote, the first cell of the newly developing individual. The mature oocyte and spermatozoa remain in a quiescent state, during which the oocyte is characterized by nuclear and cytoplasmic arrest, while the spermatozoa necessitates further maturation within the epididymis and female reproductive track prior to egg fertilization. Either in vivo or in vitro, the sperm initiates a series of irreversible biochemical and physiological modifications in the oocyte. The earliest detected signal after fertilization is cytosolic Ca2+ oscillations, a prerequisite step for embryo development. These oscillations trigger the release of the oocyte from the second meiosis arrest towards embryogenesis, also known as “oocyte activation”. Phospholipase C zeta (PLCζ) is a unique sperm-soluble protein responsible for triggering the InsP3/Ca2+ pathway within the oocyte, leading to Ca2+ oscillations and consequently to embryo development. The specific structure of PLCζ (compared to other PLCs) enables its specialized activity via the preserved X and Y catalytic domains, as well as distinct features such as rapid onset, high sensitivity to Ca2+ and cession of oscillations upon zygote formation. The emerging discoveries of PLCζ have stimulated studies focusing on the possible clinical applications of this protein in male infertility evaluation and management during IVF/ICSI. Fertilization failure is attributed to lack of oocyte second meiosis resumption, suggesting that ICSI failure may be related to impaired PLCζ activity. Microinjection of recombinant human PLCζ to human oocytes after ICSI fertilization failure may trigger Ca2+ oscillations and achieve successful fertilization, offering new hope for couples traditionally referred to sperm donation. However, more studies are still required prior to the routine implementation of this approach in the clinic. Directions for future studies are discussed.

Phospholipase C Zeta in Human Spermatozoa: A Systematic Review on Current Development and Clinical Application

“…Lastly, the C2 C-terminal domain of PLCζ is crucial for the function of PLCζ involved in targeting proteins to cell membranes. It has been shown that although the deletion of the C2 domain results in a partial loss of enzymatic activity, it has no impact on the enzyme's Ca 2+ sensitivity in vitro [16]. The mechanism of PLCZ signaling begins with the PLCζ diffusion in the ooplasm after the fusion of spermatozoa within the oocytes.…”

Artificial Egg Activation Using Calcium Ionophore

“…5 In mammals, this intracellular Ca 2+ signal is delivered in the form of a series of waves of intracellular Ca 2+ (oscillations) that begins shortly after fusion of the gametes and persists until completion of meiosis. 6 These oscillations release the oocyte from metaphase 2 meiotic arrest and initiate embryogenesis, cortical granule exocytosis, sperm nucleus decondensation, recruitment of maternal mRNA, and pronuclear development, a series of events termed “oocyte activation.” 7…”

“…6 These oscillations release the oocyte from metaphase 2 meiotic arrest and initiate embryogenesis, cortical granule exocytosis, sperm nucleus decondensation, recruitment of maternal mRNA, and pronuclear development, a series of events termed "oocyte activation." 7…”

PLCζ, WBP2NL and TNF-α expression in spermatozoa is associated with stallion fertility and seminal quality?

“…In all mammalian species studied, fertilization results in a series of intracellular calcium (Ca 2+) increases, referred to as oscillations, triggered by PLCζ , responsible for driving oocyte activation ( Bedford-Guaus et al, 2011 ). The oscillation of Ca 2+ levels plays an essential role in early embryonic development ( Gat and Orvieto, 2017 ). Lower RNA expression of PLCζ and protein levels was observed in teratozoospermic infertile men when compared with fertile patients ( Azad et al, 2018 ; Kamali-Dolat et al, 2016 ); however, no differences were detected in localization patterns ( Azad et al, 2018 ).…”