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

Sperm-specific phospholipase C zeta (PLC zeta) is widely considered to be the physiological stimulus responsible for generating calcium (Ca2+) oscillations that induce egg activation and early embryonic development during mammalian fertilization. In the mammalian testis, PLC zeta expression is detected at spermiogenesis following elongated spermatid differentiation. Sperm-delivered PLC zeta induces Ca(2+)release via the inositol 1,4,5-trisphosphate (InsP(3)) signaling pathway. PLC zeta is the smallest known mammalian PLC isoform identified to date, with the simplest domain organization. However, the distinctive biochemical properties of PLC zeta compared with other PLC isoforms contribute to its unique potency in stimulating cytosolic Ca(2+)oscillations within mammalian eggs. Moreover, studies describing PLC zeta "knockout" mouse phenotypes confirm the supreme importance of PLC zeta at egg activation and monospermic fertilization in mice. Importantly, a number of clinical reports have highlighted the crucial importance of PLC zeta in human fertilization by associating PLC zeta deficiencies with certain forms of male factor infertility. Herein, we give an update on recent advances that have refined our understanding of how sperm PLC zeta triggers Ca(2 +)oscillations and egg activation in mammals, while also discussing the nature of a potential "alternative" sperm factor. We summarise PLC zeta localization in mammalian sperm, and the direct links observed between defective PLC zeta 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.