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Uterus Development and Function
The prenatal uterus begins to develop with its formation, patterning, and fusion of Mullerian ducts. During gastrulation of the embryo, the formation of intermediate mesoderm generate the urogenital system and the female reproductive tract (FRT) is initially formed as part of it among vertebrate embryogenesis (Cunha, 1975; Kobayashi and Behringer, 2003; Spencer et al., 2012). The urogenital system will differentiate to kidneys, gonads, urinary and reproductive tracts. After that, the embryonic intermediate mesoderm proliferates and some mesenchymal cells will transit to epithelial cells which then generate the tubules that compose the male and female reproductive tracts, kidneys and gonads (Kurita, 2011). The FRT system develops primarily from Mullerian ducts and arise as cranio-caudal invaginations of thicken coelomic epithelium at the upper end of the urogenital ridge on the lateral aspect of the corresponding Wolffian duct (Spencer et al., 2012). The epithelial invaginations extend along the Wolffian ducts laterally which then extend towards the urogenital sinus to form the primordium of the FRT. Then the right and left Mullerian ducts cross the Wolffian ducts when they grow caudally to join and fuse with each other in the midline. The fusion of the Mullerian ducts, the Wolffian ducts and the urogenital sinus forms the sinovaginal bulbs. Embryos are bioptential and have both male and female reproductive tract primordial regardless of their genetic sex before sexual differentiation. As the Mullerian ducts can differentiate into oviducts, cervix, and the upper portion of the vagina as well as uterus (Cunha, 1975; Kurita, 2011; Spencer et al., 2012).
In genetic determined XX females, the absence of Y chromosome permits the bipotential gonad to differentiate into an ovary, leading to the female phenotype (Jordan and Vilain, 2002). The differentiating gonad proceeds to secret hormones which can promote sexual differentiation after gonadal gender is determined. Different from males, the differentiating ovaries in the females do not produce Mullerian inhibiting substance which can promote the differentiation and development of Wolffian ducts. So Wolffian ducts degenerate, and the ovaries remain in the female body. The portion of the female duct lateral becomes the oviduct, whereas the medial and caudal portion becomes the uterus, cervix and vagina (Cunha, 1975; Kurita, 2011; Spencer et al., 2012). In domestic animals, the Mullerian ducts fuse more posteriorly compared with rodents or higher primates, which leads to a long (pig) to medium-length (sheep and cow) bicornuate uterus with a small common corpus with a single cervix and vagina (Mossman, 1987).
Unlike most FRT organs, the organogenetic development and differentiation of uterus are not complete at birth. The uterus of laboratory rodents, domestic animals, and humans is only completely developed or differentiated postnatally (Cunha, 1976; Bartol et al., 1993; Bartol et al., 1999; Gray et al., 2001a). The histological elements of the uterus are mainly three parts: endometrium, myometrium and perimetrium. And events common to postnatal uterine morphogenesis include: 1) organization and stratification of endometrium stroma; 2) differentiation and growth of the myometrium; and 3) coordinated development of the endometrial glands (Cooke et al., 2013). The timing of these developmental events differs among species and is mainly because of differences in uterine maturity at birth. Here we mainly introduce the postnatal uterine development of ruminants, particularly, developmental events of sheep.
Ruminants have a bicornuate uterus with a small common corpus and single cervix. The uterine wall is lined by the endometrium and surrounded by myometrium outer. It is clear that the endometrium of adult sheep or cattle contains a lot of aglandular caruncles, dense stromal protuberances covered by luminal epithelium, and glandular intercaruncular areas (Wimsatt, 1950; Atkinson et al., 1984). Caruncles are the sites of superficial implantation and placentation (Wimsatt, 1950; Mossman, 1987). The gestation length of sheep is about 147 days. The vagina, cervix and oviduct, but not uterus, appear to be histologically completely developed at birth (Gray et al., 2000; Gray et al., 2001b; Carpenter et al., 2003). Postnatal uterine development mainly includes emergence and proliferation of endometrial glands, development of endometrial folds and growth of endometrial caruncles and myometrium (Wiley et al., 1987; Bartol et al., 1988a; Bartol et al., 1988b; Taylor et al., 2000). In sheep, endometrial gland genesis is initiated between postnatal day 0 (P0) and P7. Nascent glandular epithelium buds proliferate and invaginate into the stroma between P7 and P14. And tubular structures are formed coil and branch by P21. After P21, the majority developmental activity is glandular coiling and branching as these glands develop into the deeper stratum spongiosum of the stroma adjacent to the inner myometrium. By P56, the caruncular and intercaruncular endometrial areas are histoarchitecturally similar to those of the adult uterus (Cooke et al., 2013).
Uterine receptivity is a limited time period during which the uterus enters into an appropriately differentiated state that is ready to accept and accommodate a nascent embryo, resulting in a successful pregnancy (Zhang et al., 2013). Molecular and genetic evidence indicates that uterine receptivity needs the specification of autocrine, paracrine and juxtacrine factors from locally secreted cytokines, growth factors, transcription factors and ovarian hormones.
Estrogens and progesterone are the major hormones enrolled in regulating uterine receptivity (Dey et al., 2004). The uterine effects of estrogens and progesterone are mainly worked through their receptors. Recent studies have figured two types of estrogen receptors ER I/ERα and ER II/ERβ, and genes knocked out studies showed that ERα plays essential roles in uterus development as well implantation, whereas ERβ knock out uteri can still retain biological functions which allow normal implantation (Dey et al., 2004). There are two types of progesterone PRA and PRB which are expressed in the uterus. While both PRA and PRB knocked out mice show that there are many defects in ovarian and uterine functions. However, the mice which have only PRB knock out can still have normal reproductive functions (Lydon et al., 1995). These findings suggested that ERα and PRA are the primary receptors of estrogens and progesterone during uterine and ovarian development and functions.
Cytokines produced by trophoblast cells and the uterine epitheliums are also playing important roles in transforming the uterus into a receptive state as they regulate a wide type of adhesion molecules. Leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) family, binds to the LIF receptor and shares gp130 as a common signal-transduction partner with other cytokines (Wang and Dey, 2006). The role of LIF signaling in implantation is still not clear. However, recent studies showed that an optimum level of LIF is required for blastocyst implantation and other studies reported that insufficient levels or a deficiency in LIF is related with women infertility (Hambartsoumian, 1998; Ernst et al., 2001; Dey et al., 2004; Menkhorst et al., 2011; Terakawa et al., 2011). These findings provide an obvious idea that LIF is crucial for uterine receptivity and later successful implantation.
Msx1, a homeobox gene which is transiently expressed in the mouse uterine luminal epithelium and glandular epithelium during the receptive period, but its expression disappears at the time of blastocyst attachment (Daikoku et al., 2004; Zhang et al., 2013). Recent studies reported that conditional deletion of Msx1 in the uteri leads to reduced fertility due to impaired implantation. Histological analysis shows that the luminal epithelium of Msx1-/- implantation sites lacks well-defined crypts for blastocyst homing and attachment (Daikoku et al., 2011). Moreover, deletion of both Msx1 and Msx2 results in complete implantation loss with altered uterine luminal epithelium cell polarity and impaired stromal-epithelial dialogue, suggesting that the synergism effects of Msx1 and Msx2 in establishing uterine receptivity (Nallasamy et al., 2012; Zhang et al., 2013). All these results suggest that Msx1/Msx2 genes are playing essential roles in conferring murine uterine epithelial integrity and thus uterine receptivity.
It has been generally accepted that uterine receptivity is one of the most important keys to lead to the successful pregnancy in uterus. Although there are more and more advances in understanding the nature of uterine receptivity and various cellular aspects and molecular pathways have been identified, the molecular basis and crosstalk between the uterus and the blastocyst during implantation still need further exploration.
The composition of uterine secretions has been investigated during the various phases in the past years (Bell, 1988; Roberts and Bazer, 1988; Beier-Hellwig et al., 1989). The uterine secretions are rich in carbohydrates, glycoproteins and lipids. So they may provide a source of nutrients for energy and elements for anabolic pathways within the feto-placental unit. Proteins in uterine secretions serve as enzymes, carrier molecules and possible regulators of genetic activities (Bazer, 1975; Bazer et al., 2011). It is also known that uterine glands acting as a source of growth factors and cytokines which may play an essential role in regulating placental development (Hempstock et al., 2004). Previous studies showed that receptors of EGF and LIF expressed on the uterine endothelial cells. Addition of LIF has no effects on cell proliferation, but do have effects on inhibiting forskolin-induced HCG production by BeWo cells in a dose-dependent fashion (Muhlhauser et al., 1993; Kojima et al., 1995; Sharkey et al., 1999).
Endometrial secretions may also modulate maternal immunological responses with placental tissues (Hempstock et al., 2004). Glycodelin is immunosuppressive and functions as a T-cell inhibitor in the intervillous space. As gestation promotes stromal decidual cells migrate and come toile closely approximated to the basal lamina of the glandular epithelium (Seppala et al., 1998; Rachmilewitz et al., 1999; Hempstock et al., 2004). Whether these subepithelial cells play roles in immune surveillance or support the epithelium in some other way is still not clear.
It was found that estrogens can regulate uterine cell proliferation, growth, decidualization and embryo implantation. Estrogens play an important role in uterine luminal epithelium and glandular epithelium cell proliferation in mice which is mimicking that observed during the estrous cycle (Finn and Martin, 1969; Selvaraj V, 2004). Progestins inhibit the actions of estrogen in the uterus, including the induction of epithelial proliferation. The rising progesterone following ovulation inhibits E2-induced epithelial proliferation. This was demonstrated by studies in ovariectomized animals, in which treatment with progesterone abolished epithelial proliferation induced by estrogens (Finn and Martin, 1971).
It was demonstrated in mice that estrogen receptor I (ESR I) play essential role in regulating uterine epithelial proliferation as there was no proliferative response to estrogen when ESR I is knocked out (Lubahn et al., 1993). Inhibitory effects of progesterone on estrogen induced proliferation are also regulated by stromal progesterone receptor as well as the receptor located in epithelium (Cooke et al., 1997; Kurita et al., 1998; Winuthayanon et al., 2010). Interestingly, a group of scientists (Li et al., 2011) recently found a transcription factor Hand2 which is expressed in the stroma regulating progesterone’s inhibitory effects on estrogens induced uterine epithelial proliferation. This transcription factor Hand2 suppresses the production of several fibroblast growth factors which are very important for stimulating uterine epithelial proliferation. It is believed that progesterone could be used to inhibit uterine epithelial proliferation and this can provide some insights into developing experimental systems designed to block neonatal uterine development. Recently, both murine and ovine model systems have been used to show the permanent inhibition of uterine development as well as fertility requires treatments of progestins begin before the initiation of uterine gland development (Stewart et al., 2011; Filant et al., 2012). Understanding uterine development and the effects of progestins on inhibiting epithelial proliferation among different species can help to develop a rational strategy which might be need for preventing reproductive disorders in human, domestic animals and wildlife.