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All mammalian oocytes and eggs are surrounded by a relatively thick extracellular matrix (ECM), the zona pellucida (ZP), that plays vital roles during oogenesis, fertilization, and preimplantation development. Unlike ECM surrounding somatic cells, the ZP is composed of only a few glycosylated proteins, ZP1–4, that are unique to oocytes and eggs. ZP1–4 have a large region of polypeptide, the ZP domain (ZPD), consisting of two subdomains, ZP-N and ZP-C, separated by a short linker region, that plays an essential role in polymerization of nascent ZP proteins into crosslinked fibrils. Both subdomains adopt immunoglobulin (Ig)-like folds for their 3-dimensional structure. Mouse and human ZP genes are encoded by single-copy genes located on different chromosomes and are highly expressed in the ovary by growing oocytes during late stages of oogenesis. Genes encoding ZP proteins are conserved among mammals, and their expression is regulated by cis-acting sequences located close to the transcription start-site and by the same/similar trans-acting factors. Nascent ZP proteins are synthesized, packaged into vesicles, secreted into the extracellular space, and assembled into long, crosslinked fibrils that have a structural repeat, a ZP2-ZP3 dimer, and constitute the ZP matrix. Fibrils are oriented differently with respect to the oolemma in the inner and outer layers of the ZP. Sequence elements in the ZPD and the carboxy-terminal propeptide of ZP1–4 regulate secretion and assembly of nascent ZP proteins. The presence of both ZP2 and ZP3 is required to assemble ZP fibrils and ZP1 and ZP4 are used to crosslink the fibrils. Inactivation of mouse ZP genes by gene targeting has a detrimental effect on ZP formation around growing oocytes and female fertility. Gene sequence variations in human ZP genes due to point, missense, or frameshift mutations also have a detrimental effect on ZP formation and female fertility. The latter mutations provide additional support for the role of ZPD subdomains and other regions of ZP polypeptide in polymerization of human ZP proteins into fibrils and matrix.
Extracellular matrix (ECM) that surrounds most animal cells can affect cellular adhesion and migration, cell-to-cell communication, as well as gene expression, differentiation, and morphogenesis . ECM consists of proteoglycans (e.g., hyaluronic acid, heparin-, chondroitin- , and keratin-sulfate) and fibrous proteins (e.g., collagens, elastins, fibronectins, and laminins) . On the other hand, ECM of mammalian oocytes and eggs, the zona pellucida (ZP), is composed of a unique set of glycosylated proteins, ZP1–4, that differ from proteins present in somatic cell ECM .
Each ZP protein has a zona pellucida domain (ZPD) that consists of ≈270 amino acids (aa), 8 or 10 conserved cysteine (Cys) residues present as intramolecular disulfides, and two subdomains, ZP-N and ZP-C. These subdomains adopt immunoglobulin (Ig)-like folds and are connected to each other by a short, protease-sensitive linker region . Subdomain ZP-N is involved in polymerization of nascent ZP proteins into fibrils, as well as in polymerization of many other ZPD-containing proteins, such as tectorin, uromodulin, mesoglein, and cuticlins, into fibrils and matrices. Mutations in ZPD genes can result in severe human pathologies such as vascular disease, renal disease, deafness, cancer, or infertility. Although the ZP and somatic cell ECM consist of different proteins, they have certain properties in common, such as viscoelasticity that can affect cellular behavior. It has been proposed that ZP proteins self-aggregate into fibrillar structures via cross-β-sheets, similar to the structure of amyloids.
A ZP first appears as oocytes begin to grow, continues to thicken as oocytes increase in size, and is from ≈2 to ≈20 µm thick for fully grown oocytes from different mammals, e.g., the human egg ZP (hZP; ≈18 µm width) is about 3 times thicker than the mouse egg ZP (mZP; ≈6 µm width). The ZP is a viscoelastic ECM permeable to large macromolecules, (e.g., antibodies, enzymes, and small viruses) and consists of long, crosslinked fibrils that are polymers of ZP proteins. A variety of agents that do not break covalent bonds dissolve the ZP indicating that its components are held together by non-covalent interactions.
The ZP plays vital roles during oogenesis, fertilization, and preimplantation development. For example, it supports the health and growth of oocytes and follicles during oogenesis, provides species-restricted receptors for binding of free-swimming sperm to eggs during fertilization, undergoes both physical and biological changes that help to prevent polyspermy following fertilization, and protects preimplantation embryos as they traverse the female reproductive tract on their way to the uterus. In this context, it has been demonstrated that either inactivation of mZP genes or mutation of hZP genes can have a deleterious effect on ZP formation during oogenesis and can result in female infertility.
2. mZP Genes and Female Fertility and hZP Genes and Female Fertility
2.1. mZP Genes and Female Fertility
2.1.1. mZP2 and mZP3 Homozygous Nulls Are Infertile
2.2.2. mZP3 Heterozygous Nulls Are Fertile
2.2.3. mZP1 Homozygous Nulls Exhibit Reduced Fertility
2.2. hZP Genes and Female Fertility
|hZP1 Mutations||Location of Mutation||Status of Zona Pellucida||References|
|G57Dfs*9||exon-1, SC in NI befroe TD||none|||
|R61C||exon-1, NI befroe TD||none (?)|||
|W83R||exon-2, NI befroe TD||abnormal/none|||
|E67>X||exon-2, SC in NI befroe TD||none|||
|RI09H||exon-3, NI befroe TD||none|||
|H701fs*52||exon-3, SC between NI and TD||none|||
|Q292>X||exon-5, SC in ZP||none|||
|I386>X||exon-7, SC between ZP-N and ZP-C(linker)||none|||
|I390fs404X||exon-7, SC between ZP-N and ZP-C(linker)||none|||
|I390Tfs*16||exon-7, SC between ZP-N and ZP-C(linker)||none|||
|R410W||exon-7, between ZP-N and ZP-C(linker)||none|||
|W471>X||exon-8, SC in ZP-C||abnormal/none|||
|C478>X||exon-9, SC in ZP-C||none|||
|V570M||exon-11, between CFCS and EHP||none|||
|D592Gfs*29||exon-12, SC between CFCS and TMD||none|||
|R698>X||exon-19, SC between CFCS and TMD||very thin/none|||
|R349L>X||exon-8, SC at CFCS||very thin/none|||
|D100N||exon-3, NI||thin, irregular|||
|V444L||exon-10, ZP-C||thin, irregular|||
2.2.1. Infertile Women and Mutant hZP1 Genes
2.2.2. Infertile Women and Mutant hZP2, hZP3, or hZP4 Genes
3. Summary Points
The entry is from 10.3390/genes12081266
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