"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.

Keywords: Calcium oscillations; Embryogenesis; Gametogenesis; ICSI; IVF; Male infertility; Oocyte activation; PLCζ.

Fig. 1

Schematic diagram of PLCζ domains. The most conserved region among PLCs is the XY linker region, which hydrolyses PIP₂, which triggers the InsP₃/Ca²⁺ pathway [26]. The EF regions, which enhance PLCζ stability and Ca²⁺ binding, significantly contribute to the high PLCζ sensitivity to Ca²⁺ [16]. Moreover, EF domains binding to the C2 region, bend the PLCζ to a specific configuration, which exposes the catalytic X and Y domains and enables efficient PIP₂ hydrolysis [27]. The XY-linker domain is another key regulator of the catalytic domains