Proteins locally secreted in the female reproductive system
There are 39 proteins predicted to be locally secreted in the female reproductive system based on manual literature reviews and data analysis. The function of the female reproductive system is to produce oocytes, synthesize female sex hormones, carry the fetus to full term and provide nutrients to the newborn infant. The organs included in this system are the breast, cervix, endometrium, fallopian tube, ovary, placenta and vagina. Several proteins secreted in the female reproductive system are involved in placental function, breast milk production and embryonal development. Pregnancy-associated hormones and growth factors are produced and secreted by placental trophoblasts to maintain the pregnancy and regulate the nutrient and oxygen supply to the fetus. The mammary glands in lactating breasts produce and secrete milk to newborn infants. Secreted oocyte-specific proteins facilitate the fertilization and inhibit polyspermy. In the endometrial secretory phase, secreted proteins make the uterine environment suitable for pregnancy. In other words, the female reproductive system is highly dependent on complex interactions between secreted hormones, growth factors and enzymes that are required for the developing ovum or embryo, as well as the endometrial changes during the menstruation cycle.
Functions of proteins locally secreted in the female reproductive system
All proteins that are secreted in female reproductive system were classified according to function based on Uniprot molecular function and biological processes keywords. The annotations were prioritized in the following hierarchy: Blood coagulation, Complement pathway, Acute phase, Cytokine, Hormone, Neuropeptide, Growth factor, Receptor, Lectin, Transport, Developmental protein, Defence, Enzyme, Enzyme inhibitor, Transcription, Immunity, Cell adhesion. Each gene was assigned one function.
The results of the analysis are presented in Figure 1. Our analysis shows that 16 secreted proteins in the female reproductive system lack an annotated function. However, among the remaining 23 secreted proteins, we could identify several enzymes and developmental proteins that may be involved in placental development, regulation of signal proteins during pregnancy and embryogenesis. Three proteins are receptors that comprise zona pellucida and are important for fertilization. We also identified one neuropeptide which is suggested to play a role in gonadal maturation, one cell adhesion protein involved in fertilization and fetal development and a cytokine required for ovarian follicle maturation. Other secreted proteins are principal proteins in breast milk or have an unknown function.
Tissue specificity and tissue distribution classification
The genes encoding proteins locally secreted in the female reproductive system were further analyzed with regard to mRNA expression and categorized according to tissue specificity and tissue distribution. A vast majority of genes showed tissue enriched (n=28) mRNA expression, i.e. either at least four-fold higher mRNA level in one tissue compared to all other tissues (Figure 2). For most genes, mRNA was detected either in a single tissue or in a few tissues (less than 30 percent of the analyzed tissues) (Figure 3).Figure 2. Number of genes encoding proteins that are locally secreted in female reproductive system, categorized according to tissue specificity. Categories include: tissue enriched, defined as mRNA level in one tissue at least four-fold higher than in all other tissues; group enriched, defined as four-fold higher average mRNA level in a group of two to five tissues compared to all other tissues; tissue enhanced, defined as four-fold higher average mRNA level in one or more tissues compared to the mean mRNA level of all tissues; expressed in all, defined as ≥ 1 nTPM in all tissues; and not detected, defined as < 1 nTPM in all tissues.
Figure 3. Number of genes encoding proteins that are locally secreted in female reproductive system, categorized according to tissue distribution. Categories include: detected in all, defined as n=100%; detected in many, defined as 31%=< n <100%; detected in some, defined as 1< n <31%; detected in single defined as single n=1; and not detected, n=0.
Origin of proteins locally secreted in the female reproductive system
The analysis of gene expression showed that most tissue enriched proteins annotated as locally secreted in the female reproductive system are produced in the placenta (n=19), breast (n=5) or fallopian tube (n=2) (Figure 4). It should be noted that proteins specific to a certain tissue or cell types not available to the Human Protein Atlas project might appear as being enriched in tissues different from what is expected. For example, oocytes are few in relation to the total number of cells in the ovary. Furthermore, the ovary samples used in the expression level analysis are mainly derived from infertile women that lack oocytes, meaning that the final amount of oocytes sometimes may be too small in order for oocyte-specific mRNA to be detected. One example is ZP2, a likely oocyte-specific protein, which in available data was found to be tissue enriched in the brain.
Examples of secreted proteins in the female reproductive system
The main purpose of the breast is to provide nutritious milk for infants. CSN2 and CSN3 are members of the casein family and are principal proteins in mammalian breast milk. LALBA is required for lactose synthesis by forming the regulatory subunit of lactose synthetase. CSN2, CSN3 and LALBA are specifically expressed during pregnancy due to hormonal changes, which induce morphological alterations in inactive mammary glands in order to activate them and thus provide milk for infants.
The main function of the placenta is to connect the developing fetus to the mother via the umbilical cord to the uterine wall. The main cellular components of the highly vascularized placenta are trophoblasts, decidual cells, endothelial cells and primitive mesenchymal cells. An example of a secreted protein expressed in syncytiotrophoblasts includes KISS1, a stimulator of gonadotropin secretion. Extravillous trophoblasts are formed when cytotrophoblasts proliferate to form anchoring villi that attach to the uterine wall, and migrate into the decidua. An example of a secreted protein expressed in extravillous trophoblasts is PAPPA2, which is believed to be a local regulator of insulin-like growth factor.
The function of the ovary is to develop female germinal cells, oocytes, and to produce the hormones estrogen, testosterone and progesterone which are necessary for reproduction. Zona pellucida is an extracellular matrix that surrounds the oocyte and the early embryo, and is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. These glycoproteins include ZP3 and ZP4, which are believed to participate in the primary binding and induction of the sperm acrosome reaction.
The endometrium in fertile women undergoes hormone-driven cyclic regeneration, coarsely divided into a menstrual, a proliferative and a secretory phase. During the secretory phase, the remaining parts of the follicle transform into the corpus luteum which produces hormones that support the early pregnancy, or if the ovum is not fertilized, will atrophy leading to falling levels of hormones and the beginning of menstruation and a new cycle. A secreted protein expressed during the secretory phase is PAEP, a glycoprotein with essential roles in regulating a uterine environment suitable for the fertilization process and pregnancy.
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