Essential Role of Sperm-Specific PLC-Zeta in Egg Activation and Male Factor Infertility: An Update

Abstract

Sperm-specific phospholipase C zeta (PLCζ) is widely considered to be the physiological stimulus responsible for generating calcium (Ca 2+) oscillations that induce egg activation and early embryonic development during mammalian fertilization. In the mammalian testis, PLCζ expression is detected at spermiogenesis following elongated spermatid differentiation. Sperm-delivered PLCζ induces Ca 2+ release via the inositol 1,4,5trisphosphate (InsP 3) signaling pathway. PLCζ is the smallest known mammalian PLC isoform identified to date, with the simplest domain organization. However, the distinctive biochemical properties of PLCζ compared with other PLC isoforms contribute to its unique potency in stimulating cytosolic Ca 2+ oscillations within mammalian eggs. Moreover, studies describing PLCζ "knockout" mouse phenotypes confirm the supreme importance of PLCζ at egg activation and monospermic fertilization in mice. Importantly, a number of clinical reports have highlighted the crucial importance of PLCζ in human fertilization by associating PLCζ deficiencies with certain forms of male factor infertility. Herein, we give an update on recent advances that have refined our understanding of how sperm PLCζ triggers Ca 2+ oscillations and egg activation in mammals, while also discussing the nature of a potential "alternative" sperm factor. We summarise PLCζ localization in mammalian sperm, and the direct links observed between defective PLCζ protein in sperm and documented cases of male infertility. Finally, we postulate how this sperm protein can be used as a potential diagnostic marker, and also as a powerful therapeutic agent for treatment of certain types of male infertility due to egg activation failure or even in more general cases of male subfertility.

Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice

“…1 One important step toward successful fertilization is the process when sperm enter the oocyte cytoplasm and release the activation factor 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (PLCz) to trigger the calcium oscillations. 2,3 Total fertilization failure (TFF), in which all mature oocytes fail to form pronuclei, is related to many factors during in vitro fertilization (IVF) treatments. 4,5 As reported previously, defective sperm-oocyte recognition and fusion are the chief causes of TFF after IVF.…”

Sperm-oocyte interplay: an overview of spermatozoon’s role in oocyte activation and current perspectives in diagnosis and fertility treatment

“…It would be misguided to assume that only a single sperm factor activates oocytes. In the same way, other functions of these SOAF must be studied; for example, there is evidence that PLCζ has a potential role in embryonic development, particularly during the early embryonic division [ 20 , 127 ].…”

Diagnosis and Treatment of Male Infertility-Related Fertilization Failure

“…PLCζ deficiency has been observed in normozoospermic males [39][40][41] but also in patients with abnormal sperm parameters [42,43], with globozoospermia being the most characteristic example [9,44,45]. The current evidence undoubtedly supports the role of PLCζ as a protein indispensable for successful fertilization, but there are still some unknowns that remain to be solved [46,47].…”