The sperm phospholipase C-ζ and Ca2+ signalling at fertilization in mammals

Abstract

A series of intracellular oscillations in the free cytosolic Ca(2+) concentration is responsible for activating mammalian eggs at fertilization, thus initiating embryo development. It has been proposed that the sperm causes these Ca(2+) oscillations after membrane fusion by delivering a soluble protein into the egg cytoplasm. We previously identified sperm-specific phospholipase C (PLC)-ζ as a protein that can trigger the same pattern of Ca(2+) oscillations in eggs seen at fertilization. PLCζ appears to be the elusive sperm factor mediating egg activation in mammals. It has potential therapeutic use in infertility treatments to improve the rate of egg activation and early embryo development after intra-cytoplasmic sperm injection. A stable form of recombinant human PLCζ could be a prototype for use in such in vitro fertilization (IVF) treatments. We do not yet understand exactly how PLCζ causes inositol 1,4,5-trisphosphate (InsP3) production in eggs. Sperm PLCζ is distinct among mammalian PI-specific PLCs in that it is far more potent in triggering Ca(2+) oscillations in eggs than other PLCs, but it lacks a PH domain that would otherwise be considered essential for binding to the phosphatidylinositol 4,5-bisphosphate (PIP2) substrate. PLCζ is also unusual in that it does not appear to interact with or hydrolyse plasma membrane PIP2. We consider how other regions of PLCζ may mediate its binding to PIP2 in eggs and how interaction of PLCζ with egg-specific factors could enable the hydrolysis of internal sources of PIP2.

Calcium Signaling During Meiotic Cell Cycle Regulation and Apoptosis in Mammalian Oocytes

“…The OA is characterized by a sequence of morphological and molecular events that include cortical granule exocytosis, exit from M‐II arrest, extrusion of PB‐II, and formation of pronuclei (Xu et al, ; Swann and Lai, ). However, spontaneous oocyte activation (SOA) mimics all characteristics of OA process except formation of pronuclei and extrusion of PB‐II which might be due to insufficient increase of cytosolic free Ca ++ level (Cui et al, ; Premkumar and Chaube, ; Zhang et al, ).…”

“…Studies suggest that fertilizing spermatozoa trigger resumption of meiosis during oocyte activation (OA) by inducing Ca þþ release from internal stores (Swann et al, 2004;Whitaker, 2006;Machaca, 2007;Cui et al, 2013). The increased Ca þþ oscillations have been reported during sperm-induced OA and remain for several hours until pronuclei formation in several mammalian species (Vincent et al, 1992;Marangos et al, 2003;Wakai and Fissore, 2013;Ebner et al, 2015;Haverfield et al, 2016;Swann and Lai, 2016).…”

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

“…The role of intracellular Ca 2+ and inositol 1,4,5-triphosphate (InsP 3 ) within the fertilized eggs has been at the forefront of recent research [19]. That signal transduction pathway involved in many biological processes, is first initiated by phospholipase C (PLC) isoforms, which hydrolyze the precursor phosphatidylinositol 4,5-biphosphate (PIP 2 ), resulting in the formation of InsP 3 and diacylglycerol (DAG).…”

“…Initial studies relied on the predominant hypothesis that the sperm activates the egg via binding to the egg membrane. Only later, researchers demonstrated that InsP 3 production and subsequent Ca 2+ oscillations are triggered by a sperm-derived soluble protein which is released to the oocyte cytoplasm immediately after sperm-egg fusion [19, 21]. …”

Molecular triggers of egg activation at fertilization in mammals

“…It may be possible that some cases of total fertilization failure that occur following ICSI treatment in the clinic could be a result of reduced levels of PLCζ in the patient's sperm. The clinical applications for PLCζ have been discussed thoroughly in a number of reviews (Ramadan et al 2012, Kashir et al 2012a, Nomikos et al 2013a, Swann & Lai 2016.…”