Signal transduction in mammalian oocytes during fertilization

Abstract

Mammalian embryo development begins when the fertilizing sperm triggers a series of elevations in the oocyte's intracellular free Ca(2+) concentration. The elevations are the result of repeated release and re-uptake of Ca(2+) stored in the smooth endoplasmic reticulum. Ca(2+) release is primarily mediated by the phosphoinositide signaling system of the oocyte. The system is stimulated when the sperm causes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG); IP3 then binds its receptor on the surface of the endoplasmic reticulum that induces Ca(2+) release. The manner in which the sperm generates IP3, the Ca(2+) mobilizing second messenger, has been the subject of extensive research for a long time. The sperm factor hypothesis has eventually gained general acceptance, according to which it is a molecule from the sperm that diffuses into the ooplasm and stimulates the phosphoinositide cascade. Much evidence now indicates that the sperm-derived factor is phospholipase C-zeta (PLCζ) that cleaves PIP2 and generates IP3, eventually leading to oocyte activation. A recent addition to the candidate sperm factor list is the post-acrosomal sheath WW domain-binding protein (PAWP), whose role at fertilization is currently under debate. Ca(2+) influx across the plasma membrane is also important as, in the absence of extracellular Ca(2+), the oscillations run down prematurely. In pig oocytes, the influx that sustains the oscillations seems to be regulated by the filling status of the stores, whereas in the mouse other mechanisms might be involved. This work summarizes the current understanding of Ca(2+) signaling in mammalian oocytes.

Keywords: Embryo; Fertilization; Oocyte; Signal transduction; Sperm.

Fig. 1

Schematic illustration of various hypotheses explaining the way the fertilizing sperm induces an elevation in the intracellular free Ca²⁺ concentration of the oocyte. The Ca²⁺ bomb hypothesis proposes that the sperm delivers a bolus of Ca²⁺ that causes Ca²⁺-induced Ca²⁺ release in the oocyte. According to the Ca²⁺ conduit model, the sperm facilitates Ca²⁺ entry from the extracellular medium. The receptor hypothesis suggests that Ca²⁺ release is induced when the sperm interacts with an oocyte receptor leading to the generation of IP₃, the Ca²⁺ releasing second messenger. Finally, the sperm factor hypothesis claims that a factor from the sperm diffuses into the ooplasm and causes the production of IP₃ to mobilize Ca²⁺

Fig. 2

Hypothetical mechanism of PLCζ-induced Ca²⁺ release. Following gamete fusion, PLCζ diffuses into the ooplasm and hydrolyses PIP₂ located in the membrane of cytoplasmic vesicles. It is possible that it binds to a yet-to-be-identified protein in the vesicular membrane (symbolized by a red rectangle). The IP₃ generated as a result of the hydrolysis moves to the endoplasmic reticulum and induces the release of stored Ca²⁺. Elevated Ca²⁺ levels lead to increased PLCζ activity, which, through a positive feedback loop, stimulates further increase of Ca²⁺ and IP₃ (from Swann and Lai , with permission)