The mammalian egg's zona pellucida, fertilization, and fertility.

Abstract

The zona pellucida (ZP) is a relatively thick extracellular matrix (ECM) that surrounds all mammalian eggs and plays vital roles during oogenesis, fertilization, and preimplantation development. The ZP is a semi-permeable, viscous ECM that consists of three or four glycosylated proteins, called ZP1-4, that differ from proteoglycans and proteins of somatic cell ECM. Mammalian ZP proteins are encoded by single-copy genes on different chromosomes and synthesized and secreted by growing oocytes arrested in meiosis. Secreted ZP proteins assemble in the extracellular space into long fibrils that are crosslinked polymers of ZP proteins and exhibit a structural repeat. Several regions of nascent ZP proteins, the signal-sequence, ZP domain, internal and external hydrophobic patches, transmembrane domain, and consensus furin cleavage-site regulate secretion and assembly of the proteins. The ZP domain is required for assembly of ZP fibrils, as well as for assembly of other kinds of ZP domain-containing proteins. ZP proteins adopt immunoglobulin (Ig)-like folds that resemble C- and V-type Ig-like domains, but represent new immunoglobulin-superfamily subtype structures. Interference with synthesis, processing, or secretion of ZP proteins by either gene-targeting in mice or mutations in human ZP genes can result in failure to assemble a ZP and female infertility. ZP2 and ZP3 must be present to assemble a ZP during oocyte growth and both serve as receptors for binding of free-swimming sperm to ovulated eggs. Acrosome-reacted sperm bind to ZP2 polypeptide by inner-acrosomal membrane and acrosome-intact sperm bind to ZP3 oligosaccharides by plasma membrane overlying the sperm head. Binding of acrosome-intact sperm to ZP3 induces them to undergo cellular exocytosis, the acrosome reaction. Only acrosome-reacted sperm can penetrate the ZP, bind to, and then fuse with the egg's plasma membrane to produce a zygote. Following sperm-egg fusion (fertilization) the ZP undergoes structural and functional changes (zona reaction) induced by cortical granule components (cortical reaction) deposited into the ZP. The latter include zinc and ovastacin, a metalloendoprotease that cleaves ZP2 near its amino-terminus and hardens the egg's ZP. The changes prevent penetration of bound sperm through and binding of supernumerary sperm to the ZP of fertilized eggs as part of a secondary or slow block to polyspermy. Therefore, ZP proteins act as structural proteins and sperm receptors, and help to prevent fertilization by more than one sperm. Here we review some of this information and provide details about several key features of ZP proteins, ZP matrix, and mammalian fertilization.