Abstract
All mammalian uteri contain glands in the endometrium that develop only or primarily after birth. Gland development or adenogenesis in the postnatal uterus is intrinsically regulated by proliferation, cell–cell interactions, growth factors and their inhibitors, as well as transcription factors, including forkhead box A2 (FOXA2) and estrogen receptor α (ESR1). Extrinsic factors regulating adenogenesis originate from other organs, including the ovary, pituitary, and mammary gland. The infertility and recurrent pregnancy loss observed in uterine gland knockout sheep and mouse models support a primary role for secretions and products of the glands in pregnancy success. Recent studies in mice revealed that uterine glandular epithelia govern postimplantation pregnancy establishment through effects on stromal cell decidualization and placental development. In humans, uterine glands and, by inference, their secretions and products are hypothesized to be critical for blastocyst survival and implantation as well as embryo and placental development during the first trimester before the onset of fetal–maternal circulation. A variety of hormones and other factors from the ovary, placenta, and stromal cells impact secretory function of the uterine glands during pregnancy. This review summarizes new information related to the developmental biology of uterine glands and discusses novel perspectives on their functional roles in pregnancy establishment and success.
Essential Points
Uterine gland development or adenogenesis occurs primarily after birth and is initially ovary- and steroid-independent, but particularly susceptible to programming by exposure to steroid hormones or endocrine-disrupting compounds
Uterine adenogenesis is intrinsically regulated by proliferation, cell–cell interactions, growth factors, such as WNTs and their inhibitors, as well as forkhead box A2 (FOXA2) and estrogen receptor α (ESR1) transcription factors
Extrinsic factors regulating uterine adenogenesis originate from the ovary and pituitary as well as maternal mammary gland
Uterine glands are essential for fertility and pregnancy success in the adult, as their secretions and products impact embryo survival and implantation in domestic animals and stromal cell decidualization and placental development in mice
Analysis of human implantation sites supports a role for uterine gland secretions or histotroph for embryo and placental development during the first trimester, prior to the onset of fetal–maternal circulation
Defects in uterine gland development and/or function may be causative factors for pregnancy loss and later pregnancy complications such as preeclampsia and fetal growth retardation
Increased knowledge of uterine gland biology is critical to understanding and diagnosing pregnancy loss, developing therapies for the restoration of endometrial function, and treating fertility problems and disease in women
The uterus is part of the female reproductive tract (FRT) and consists of two different layers (endometrium and myometrium). The endometrium contains many different types of cells (epithelium, stroma, immune, endothelium), with the epithelium comprised of two distinctive cell types [luminal epithelium (LE) and glandular epithelium (GE)]. The idea that the glands of the uterus produce factors essential for pregnancy success evolved over many centuries [see Refs. (1–5)]. During the past few decades, evidence has accumulated in primate and subprimate species supporting an unequivocal role for uterine glands and their secretions, termed histotroph, as principal regulators of conceptus (embryo/fetus and associated extraembryonic placental membranes) survival, development, implantation, and placentation. Studies on sheep and mice devoid of uterine glands provide direct evidence that their secretions and products impact conceptus survival and growth, uterine receptivity, stromal cell decidualization, and placental growth. Contemporary studies of human implantation sites discovered that conceptus trophoblast cells associate with uterine glands and direct their secretions into the developing placenta. These observations support the hypothesis that gland-derived histotroph is critical for human conceptus survival and growth during the first trimester prior to the establishment of maternal blood flow toward the placenta. This review summarizes new information related to the developmental biology of uterine glands and discusses novel perspectives on their functional roles in pregnancy establishment and success.
Developmental Biology of Uterine Glands
The organogenesis and differentiation of most FRT organs are completed during prenatal development (6–10). However, the uterus is neither fully developed nor differentiated at birth in domestic and laboratory animals as well as humans (1, 2, 11–16). Events common to postnatal uterine development in laboratory rodents and domestic animals include: organization and stratification of the mesenchyme and/or endometrial stroma; myometrial differentiation and growth; and differentiation and development of glands within the endometrium (Fig. 1).
Figure 1.
Uterine morphology, radial patterning, and postnatal development in mice and sheep. (a) Diagrams of ideal frontal sections of uterine types. The drawings cut the oviducts off near the uterotubal junctions, and the vagina just caudal to the cervix. Rodents (rats and mice) have a long duplex type of uterus with dual cervices. Sheep have a medium-length bicornuate type of uterus and a short uterine body and a single cervix. (b) Diagrams of ideal radial patterns of the uterine wall. The curved lines in the endometrium denote the tubular, coiled, and slightly branched glands that extend from the uterine lumen to the inner layer of myometrium. The mouse uterus lacks appreciable glands in the upper third of the endometrium on the mesometrial area of the uterus. The sheep uterus contains large number of glands in the intercaruncular areas of the endometrium, whereas the caruncles are glandless. (c) Immunofluorescent localization of forkhead box a2 (FOXA2) and keratin (KRT8) was performed for sections of the postnatal mouse uterus, whereas only FOXA2 was localized in the sheep uterus. Note the expression of FOXA2 in nascent and developing glands. Sections were counterstained with 4′,6-diamidino-2-phenylindole (DAPI) to visualize all nuclei. Scale bar, 100 μm (mouse) and 50 μm (sheep). Car, caruncle; M, myometrium; P, postnatal day; S, stroma.
The original descriptions of uterine gland development or adenogenesis after birth and the architecture of glands in the adult uterus relied on two-dimensional histology (Fig. 1). During the first or second week of postnatal life, adenogenesis is initiated by differentiation of the GE from precursor LE. Nascent glands elongate into the stroma and then coil and slightly branch as they develop through the stroma toward the inner circular layer of the myometrium. Distinctively, gland development is limited to intercaruncular areas of the endometrium of ruminants (sheep, cattle, deer), as the aglandular caruncles are the site of placentation (17). In mice and rats, adenogenesis occurs primarily in the lateral and antimesometrial areas of the uterus, as the upper mesometrial area of the endometrium is devoid of glands. Recent advances in tissue clearing and microscopy have provided three-dimensional (3D) models of uterine gland architecture in prepubertal and adult mice (18–21). At birth [postnatal day (P)0], no rudimentary gland buds are present (Fig. 2). Bud- and teardrop-shaped epithelial invaginations become evident between P7 and P9 and form elongated tubes by P14. As the new glands elongate, they become coiled and sinuous. By P21, the histoarchitecture of the uterus resembles that of the adult, containing glands that are coiled and slightly branched.
Figure 2.
Overview of uterine gland development in the mouse before puberty. (a) Dark-field images of the uterine epithelium isolated before (P5) and during genesis and budding of the glands from the LE (denoted by an asterisk). (b) Overview of uterine gland morphogenesis based on postnatal age, two-dimensional histology, and 3D imaging as proposed by Vue et al. (18).
Our understanding of genetic and physiological pathways that regulate the formation, patterning, and differentiation of the uterus and, in particular, adenogenesis has significantly relied on the study of model organisms given the difficulty and ethical concerns of studying the human (8, 22). Findings in laboratory and domestic animals support the ideas that postnatal uterine development is multifaceted and governed by intrinsic genetic cascades, cell proliferation, and cell–cell interactions as well as extrinsic factors from the ovary, pituitary, and mammary gland that cooperate to achieve a fully developed and mature organ capable of supporting a pregnancy. The identification of genes and gene networks involved in organogenesis and morphogenesis of the uterus has greatly benefited from mouse genetic models and, more recently, conditional deletion approaches employing Cre drivers to delete floxed alleles in almost all uterine cell types or only the epithelia or stroma. In particular, the progesterone receptor (Pgr) Cre (Pgr-Cre) mouse has been invaluable to study postnatal uterine development, because Cre excision activity occurs only after birth and is restricted to cells that express the Pgr, including the uterus, ovary, oviduct, pituitary gland, and mammary gland (23). In the neonatal uterus of Pgr-Cre mice, Cre excision activity begins in the LE of the uterus by P5 prior to initiation of adenogenesis (24). Thus, Pgr-Cre mice are particularly useful to study genes in the postnatal or adult uterus that are embryonic lethal.
Intrinsic regulatory mechanism
Development of the uterus depends on cell–cell interactions for local control and coordination of morphogenetically important cell behaviors, including differentiation, proliferation, and movement (25–27). Proliferation of the LE, as well as nascent and budding GE, is observed in the neonatal uterus of mice, sheep, and pigs (28, 29). A recent study suggested that a critical epithelial population in the uterus must be reached for adenogenesis to proceed normally in mice (24). Growth of budding glands into the stroma also involves alterations in the basal lamina that permit and direct GE cell migration into the underlying stroma (30–32). A number of intrinsic growth factors have been implicated in postnatal uterine adenogenesis, including wingless-type mouse mammary tumor virus integration site family (WNT), hepatocyte growth factor, fibroblast growth factors (FGFs), IGFs, and matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase [see (1–3, 7, 8, 13, 33)].
WNTs
The Wnt family of genes encodes a group of 19 highly conserved, secreted signaling molecules that are homologous to the Drosophila melanogaster segment polarity gene wingless and critical regulators of cell fate, growth, and differentiation as well as cell–cell interactions in many different organs (34). Defects in uterine gland development occur in Wnt7a, Wnt5a, and Wnt4 mutants as well as in mice harboring mutation in Wnt downstream effectors, catenin (cadherin-associated protein) β1 (Ctnnb1) and lymphoid enhancer binding factor (Lef) 1 (35–39). WNT signaling is categorized as either canonical or noncanonical (40) [Fig. 3(a)]). Both pathways are initiated by Wnt ligands binding to frizzled (Fzd) receptors. The canonical Wnt pathway leads to Ctnnb1:T-cell factor/Lef–mediated gene expression, which regulates proliferation and differentiation of cells [Fig. 3(a)]. CTNNB1 is also involved in regulation and coordination of cell–cell adhesion as a component of adherens junctions. Of note, conditional deletion of Ctnnb1 or cadherin 1 (Cdh1), a critical component of adherens junctions, in the mouse uterus after birth using Pgr-Cre completely inhibited gland development (41, 42). The noncanonical Wnt pathway is mediated by intracellular calcium ion and c-Jun N-terminal kinase. This signaling leads to nuclear factor of activated T-cells (NFAT), a critical transcriptional factor regulating gene expression, and activation of the planar cell polarity pathway regulating the actin cytoskeleton that modulates cell polarity and motility. Noncanonical Wnt signaling is required for tissue formation in many organs (40).
Figure 3.
Proposed source and actions of the WNT signaling system in postnatal uterine development in mice and sheep. (a) Schematic illustrating the canonical and noncanonical WNT signaling pathways and inhibition of those pathways by DKK and SFRP. Activation of the canonical signaling stimulates epithelial adhesion and proliferation as well as stromal cell proliferation in the intercaruncular endometrium. Activation of the noncanonical pathway would stimulate epithelial cell migration and movement. (b) Autocrine and paracrine actions of WNTs and their inhibitors in the neonatal mouse uterus. The upper panel displays immunofluorescent localization of forkhead box A2 (FOXA2) and keratin (KRT8) in the adult mouse uterus; note that FOXA2 is only expressed in the glands. In the lateral and antimesometrial (AM) stroma, WNTs expressed in the LE and stroma may have autocrine or paracrine actions on the LE, stroma, and/or GE to promote uterine adenogenesis. However, the WNT inhibitor DKK2 is expressed predominantly by the stroma of the mesometrial area (M) and myometrium that inhibits WNT signaling and thus inhibiting GE growth and development in the upper mesometrial area of the endometrium as well as the myometrium. Original magnification, ×10. (c) Autocrine and paracrine actions of WNTs and their inhibitors in the neonatal ovine uterus. The upper panel displays immunolocalization of FOXA2 in the uterus of a P14 ewe; note that FOXA2 is only expressed in the glands. In the intercaruncular endometrium, WNTs expressed in the LE (WNTs 5A, 7A, and 11) may have autocrine or paracrine actions on the LE or stroma, respectively. WNT2B is expressed only in the stroma and may have autocrine or paracrine actions on the stroma or the LE and GE, respectively. WNT5A is expressed predominantly by the GE and may have autocrine or paracrine actions on the GE or stroma, respectively. SFRP2 is expressed predominantly by the stroma of the caruncles as well as by the intercaruncular stroma between the tips of the glands and the inner circular layer of the myometrium. Binding of the FZD receptors for the WNTs on the epithelia and stroma inhibit epithelial growth and development into the caruncular areas of the endometrium as well as the myometrium. Scale bar, 50 μM. ABC, active β-catenin; Car, caruncle; CDH1, cadherin 1; DKK, dickkopf; DVL, dishevelled; FZD, frizzled receptor; GSK3B, glycogen synthase kinase 3β; LGR, leucine-rich repeat–containing G protein–coupled receptor; LPR, lipoprotein receptor-related protein; RSPO, roof plate–specific spondin; SFRP, secreted FZD-related protein; TCF, transcription factor.
In the developing mouse uterus, Wnt7a is only expressed in the endometrial LE, whereas Wnt4 and Wnt5a are predominantly expressed in the endometrial stroma (43–45). Wnt7a-null mice are viable, but mutant females display abnormal morphogenesis along the anterior–posterior and radial axes of the uterine horn after birth (44). The adult Wnt7a-null uterus has a stratified squamous LE (in contrast to simple columnar) surrounded by a small stromal layer that does not contain glands (43, 46). Because Wnt7a is expressed in the Müllerian duct epithelium, the Pgr-Cre mouse model was used to produce a conditional knockout (cKO) of Wnt7a (36). The uteri of Pgr-Cre:Wnt7a cKO mice contained no endometrial glands, whereas all other cell types appeared normal with no evidence of a stratified squamous LE. These studies support the idea that Wnt7a coordinates a variety of cell and developmental pathways that guide postnatal uterine differentiation and growth (47).
Wnt5a-null mice have short and coiled uterine horns of normal diameter at birth (37). Given that the Wnt5a-null mice perish immediately after birth, their reproductive tract was xenografted into adult hosts to assess postnatal development. Although the oviduct, uterus, and cervix of the FRT developed in the absence of Wnt5a, the xenografted mutant uterus failed to form glands. Wnt4-null females lack Müllerian and Wolffian ducts and die shortly after birth (48). The Pgr-Cre:Wnt4 cKO uterus possessed a pseudostratified LE with decreased gland number (35). Cell-specific conditional and inducible deletion studies in the developing mouse uterus are needed to precisely investigate the function of Wnts and other morphoregulatory genes because adenogenesis in the uterus is inhibited when the LE changes identity and becomes stratified during the first week after birth (9).
The canonical WNT signaling pathway is particularly crucial for uterine adenogenesis. Using Pgr-Cre mice, Jeong et al. (41) found that expression of a dominant stabilized form of CTNNB1 resulted in endometrial gland hyperplasia, whereas ablation of Ctnnb1 inhibited endometrial gland development and induced squamous cell metaplasia. Both Lef1 and cyclin D1 are expressed in nascent and budding glands of the neonatal mouse uterus, and null Lef1 mutants fail to develop glands in their uterus after birth (38). The porcupine homolog (Porcn) is a membrane-bound O-acyltransferase that acylates all mammalian WNTs (49, 50), which is required for WNT secretion and binding to their cognate FZD receptor on target cells (51, 52). To inactivate all secreted WNTs, Pgr-Cre mice were used to conditionally delete Porcn (53). The Pgr-Cre:Porcn cKO mice displayed normal prepubertal uterine development, but defects in gland maintenance and stromal cell proliferation in the adult. Intriguingly, intrauterine injections of Wnt7a into the uterine horn of adult Pgr-Cre:Porcn cKO mice increased gland formation, whereas intrauterine injections of Wnt5a did not stimulate gland development, but they did stimulate proliferation of the LE and stroma (53). Of note, Pgr-Cre:Wnt5a cKO mice exhibit aberrant glandular development on the mesometrial side of the uterus (54).
Leucine-rich repeat–containing G protein–coupled receptor (Lgr) 4 and its homolog Lgr5 were identified as receptors of roof plate–specific spondins (R-spondins), which are secreted Wnt pathway agonists and potentiators of canonical Wnt signaling (55, 56). In the adult mouse uterus, Lgr4 is expressed in the LE, GE, and myometrium (57). Conditional deletion of Lgr4 was conducted using keratin 5–Cre mice that deletes genes in the LE and GE of the uterus. Few if any glands were observed in the P21 keratin 5–Cre:Lgr4 cKO uterus, and no glands were observed in the adult (57). Thus, canonical and noncanonical WNT signaling have exclusive and cooperative roles in uterine epithelial morphogenesis and growth in the neonatal mouse.
Differential WNT signaling activity limits uterine gland development to discrete areas of the endometrium in both mice and sheep [Fig. 3(b) and 3(c)]. In the neonatal mouse uterus, active WNT signaling activity was discovered to be progressively restricted to epithelia in the lateral and antimesometrial areas of the uterus (21). Expression of dickkopf 2 (Dkk2), a secreted potent WNT inhibitor that antagonizes canonical WNT signaling by inhibiting WNT ligand interactions with the coreceptors low-density lipoprotein receptor–related protein (LRP) 5 and LRP6 (58), is confined to the stroma of the aglandular mesometrial area and myometrium of the uterus (21) [Fig. 3(b)]. Of note, progesterone treatment of newborn mice induced Dkk2 in the antimesometrial area of the uterus in concert with inhibition of gland genesis (21).
In the neonatal sheep uterus, in situ hybridization studies found that WNT5A, WNT7A, and WNT11 were expressed in uterine epithelium, whereas WNT2B was expressed in the stroma (59) [Fig. 3(c)]. The WNT receptors FZD2 and FZD6 were detected in all uterine cell types, with FZD6 being particularly abundant in endometrial epithelia. In the same regard, coreceptor LRP6 was detected in all uterine cells. Expression of secreted FZD-related protein (SFRP) 2, a soluble WNT antagonist, was abundant in the stroma of the aglandular areas of the endometrium, termed caruncles, between P7 and P56. Thus, caruncular SFRP2 expression may provide a spatial mechanism to restrict active WNT signaling and adenogenesis to the intercaruncular areas of the uterus. Of note, estrogen-induced disruption of adenogenesis was associated with aberrant induction of SFRP2 and decreased WNT expression in the uterus (59). Thus, WNT signaling appears to define morphogenetically active areas of the endometrium that are permissive to uterine adenogenesis in the developing uterus of both sheep and mice.
Transcription factors
Forkhead box A2.
FOX (forkhead box) A transcription factors comprise a subfamily of forkhead transcription factors that contain high homology in the winged helix DNA-binding domain and are termed “pioneer” transcription factors, as they can facilitate the binding of other transcription factors to compacted chromatin (60). The FOXA family of transcription factors includes FOXA1, FOXA2, and FOXA3 (previously termed HNF3α, HNF3β, and HNF3γ, respectively) (61), and these factors have essential roles in regulating expression of genes involved in cell growth, proliferation, differentiation, and longevity in several organs and tissues (60–63). In mice, Foxa2 is the only family member expressed in the uterus, and it is expressed explicitly in nascent, developing, and differentiated glands (64, 65) (Figs. 1 and 3). Foxa2-null mice die at embryonic day 10 or 11 due to severe defects in the notochord, neural tube, and gut tube formation (66). To obviate embryonic lethality, Foxa2 was conditionally ablated in the uterus immediately after birth using the Pgr-Cre mouse (67). In the Pgr-Cre:Foxa2 cKO uterus, gland differentiation was inhibited, rendering adult mice glandless and infertile. Of note, the original report of Jeong et al. (67) found that some Pgr-Cre:Foxa2 cKO mice had glands, but recent studies with those mice found no evidence of glands (68–70). The differences in the phenotype of the Pgr-Cre:Foxa2 cKO mice could be due to genetic background and the environment as well as changes in the diet and microbiota (71, 72).
FOXA2 is expressed solely in the glands of the developing and adult uterus of both mice and sheep [Fig. 3(b) and 3(c)] as well as pigs, cattle, and humans (3, 73). Thus, FOXA2 is postulated to be a conserved critical transcription factor controlling the differentiation and function of uterine GE in all mammals. In many other organs, such as the liver, lung, and pancreas, Foxa2 has an essential role in epithelial budding and morphogenesis (61). Integrated chromatin immunoprecipitation sequencing and cell-specific gene expression profiling have identified many potential Foxa2-regulated genes and biological pathways (cell cycle, cell junction, focal adhesion, and WNT signaling) in the developing neonatal mouse uterus (65, 69). FOXA2 regulates expression of multiple WNTs in other organs, including Wnt3a, Wnt7b, and Wnt8a (74–76). Furthermore, CTNNB1 can promote Foxa2 expression in the prostate, indicating a reciprocal interaction between FOXA2 and WNT signaling (77). Recently, ablation of sex determining region Y (SRY)-box 17 (Sox17) using Pgr-Cre mice was found to phenocopy Foxa2 ablation, indicating that it may regulate Foxa2 expression in the nascent GE cells within the LE, but the underlying mechanism is yet to be defined (78, 79). Determination of the mechanism of how FOXA2 is transcriptionally regulated as well as the genes regulated by FOXA2 should reveal critical biological pathways governing postnatal uterine gland morphogenesis and function (69).
Distal-less homeobox genes.
The distal-less homeobox (Dlx) gene family includes three bigenic clusters (Dlx1/2, Dlx3/4, Dlx5/6) that comprise a highly conserved family of homeobox genes homologous to the distal-less (Dll) gene of Drosophila. Genetic disruption of Dxl5/6 leads to perinatal death, limb malformations, and defects in craniofacial development (80, 81). Dlx5 and Dlx6 are expressed in the LE and developing GE in the postnatal mouse uterus as well as in the GE of the human adult uterus (82). Conditional deletion of Dxl5 and Dxl6 using Pgr-Cre mice severely impaired gland development in the neonate and resulted in complete infertility in the adult (82). Genes involved in postnatal uterine adenogenesis (Foxa2, Wnt7a) were dysregulated in Dxl5/6 cKO mice. Thus, Dxl5 and Dxl6 may be upstream of key developmental genes controlling epithelial morphogenesis in the neonatal mouse uterus.
Estrogen receptor α.
Adenogenesis in neonatal rodent (83–85), pig (86, 87), and sheep (29) uteri involve coordinated changes in epithelial phenotype that are marked by estrogen receptor α (ESR1) expression in nascent and proliferating glands. Neither Esr1 or Esr2 is essential for organogenetic development and patterning of the Müllerian duct in the fetus (88–90); however, Esr1 is essential for uterine growth and development in mice after birth (89). The initial stages of uterine development and adenogenesis from birth (P0) to P10 occur normally in Esr1-null mice (91). Uterine epithelial proliferation and gland development were also similar in Esr1-null and wild-type mice from P2 to P22 (92). After a nadir of proliferation around P22, uterine cells begin to proliferate again and uterine weight increases (28), presumably as a result of increased estrogen secretion between P26 and P29 (93, 94). However, Esr1-null mice exhibited little LE proliferation and a considerable loss of glands by P60 compared with wild-type mice (92). Thus, Esr1 is dispensable for the initiation of gland genesis in the neonate, but necessary for the maintenance of developed uterine glands after P22 and further increases in gland number as the mice attain puberty.
In sheep treated with the antiestrogen EM-800, a pure ESR1 antagonist, from birth, uterine growth was not affected on P56 (95). However, the intercaruncular endometrium contained fewer ductal gland invaginations, and endometrial glands were less coiled and branched in EM-800–treated ewes as compared with control ewes. In contrast to mice and sheep, ESR1 has a crucial regulatory role in uterine development in the newborn pig. Administration of the antiestrogen ICI 182,780, a potent ESR1 antagonist, from birth inhibited uterine adenogenesis and overall growth at P14 in neonatal gilts (86). Thus, uterine ESR1 expression and activation are important elements of the organizational program that determines patterns of uterine growth and adenogenesis in an age- and species-dependent manner.
Elegant tissue recombination studies involving mouse uterine stroma and epithelium indicate that epithelial ESR1 is neither necessary nor sufficient to mediate the mitogenic actions of estrogen (96, 97). Instead, the proliferative effects of estrogen on epithelium appear to be mediated primarily by stromal ESR1 via production of paracrine-acting, stromal-derived growth factors such as epidermal growth factor (EGF), IGF1, and IGF2 (96, 98–100). The precise biological roles and significance of ligand-dependent and ligand-independent actions of ESR1 and stromal–epithelial interactions in uterine gland morphogenesis and growth remain to be determined.
Extrinsic Regulatory Mechanisms
Evidence in domestic and laboratory animals established that postnatal uterine development and adenogenesis are regulated by extrinsic factors that originate from a number of sources, including the pituitary and ovary as well as the maternal mammary gland.
Pituitary prolactin
Prolactin (PRL) is a member of a unique hormone family that includes chorionic somatomammotropin hormone 1 (CSH1; originally termed placental lactogen) and GH based on genetic, structural, binding, receptor signal transduction, and function studies (101). These hormones regulate the growth and differentiation of many epithelial-mesenchymal organs, including the mammary gland (101–103). Circulating levels of PRL in ewe lambs are relatively high on P1, increase to a maximum on P14, and then decline slightly to P56 (29, 104). Expression of the PRL receptor (PRLR) is restricted to nascent GE buds on P7, and proliferating and differentiating GE from P14 to P56 (29). Hyperprolactinemia, induced in neonatal ewes by treatment with recombinant ovine PRL from birth to P56, increased uterine gland number by >60% (104). Furthermore, induction of hypoprolactinemia using bromocriptine, an inhibitor of pituitary PRL secretion, in neonatal ewes from birth to P56 reduced uterine glands by 35% (104). Those effects of PRL on the neonatal ovine uterus were mediated by activation of the Janus kinase–signal transducer and activator of transcription (JAK-STAT) as well as MAPK pathways that impact cell growth and differentiation. How PRL and its receptor impact gland development and function in other mammals is not well understood. The PRLR is expressed explicitly in the glands of the human uterus (105), but not in the mouse uterus (106).
Ovary and its hormones
Data for several species, including the mouse (107), rat (108), sheep (31, 109), and pig (12, 87), indicate that uterine growth and morphogenesis, marked by the genesis and development of nascent glands, proceed normally for a period of time after bilateral ovariectomy at birth. Although initial gland genesis is ovary-independent, studies in sheep and mice support the concept that estrogens and other unknown factors from the ovary act in an endocrine manner to impact prepubertal uterine adenogenesis and growth.
Sheep
The newborn sheep ovary contains significant numbers of growing and antral ovarian follicles at birth (∼455 and 935 per ovary, respectively) that increase in number by P28 ∼683 and 1100 per ovary), and then decline in number by P84 (∼100 and 287 per ovary) (110, 111). There is no evidence that those ovarian follicles secrete appreciable amounts of estrogens between birth and puberty, as aromatase (CYP19A1) expression is not detectable in the granulosa cells and circulating estrogen levels are negligible (110, 112, 113).
Ovariectomy of ewe lambs at birth did not affect initial adenogenesis on P14 (31), whereas ovariectomy on P7 reduced uterine growth as well as the number of glands on P56 (112). Candidate ovarian-derived factors from the growing and antral follicles include follistatin, activins, and inhibin as well as IGFs (111, 112). Of note, the activin–follistatin system is present in both the uterus and ovary of neonatal ewes (112, 113). The Inverdale gene mutation (FecXI) in sheep results in an increased ovulation rate in heterozygous ewes, but homozygous Inverdale ewes (II) are infertile with “streak” ovaries that lack normal developing preantral and antral follicles (114). When compared with wild-type ewes on P56, uterine growth of homozygous Inverdale ewes was reduced, and the endometrium contained fewer glands (113). Although circulating concentrations of estrogen in neonatal ewes were low to undetectable, homozygous Inverdale ewes had lower concentrations of testosterone and inhibin-α between P14 and P56. Thus, developing preantral and/or antral ovarian follicles secrete endocrine-acting factors that stimulate uterine growth and adenogenesis in neonatal ewes. The precise nature of those factors is not known, but they are not estrogens and could be activins or follistatin from the large number of ovarian follicles.
Rodents
In the neonatal rat, normal uterine growth and differentiation are independent of the ovaries and adrenals before P10, and uterine growth and adenogenesis are not appreciably affected by ovariectomy on P6 when assessed on P25 (108). Similarly, normal uterine growth and differentiation were observed in neonatally ovariectomized mice until P25 (28). However, a recent study found that uterine growth and gland maintenance after P21 requires the ovary (91). The nature of the ovarian-derived factors impacting uterine growth and development after weaning is not known, but a strong candidate factor is estrogen or an estrogen-regulated growth factor given postnatal changes in circulating estrogen and the influence of Esr1 on uterine gland maintenance (92). Of note, Bigsby et al. (115) grafted whole pieces of the neonatal uterus from wild-type or Esr1-null mice into syngeneic wild-type or Esr1-null adult host mice. Using an ovariectomy and hormone replacement approach, estrogen-stimulated proliferation of Esr1-null uterine grafts was apparent, but only when they were grown in wild-type hosts. These observations support the idea that estrogen stimulates the production of a systemic growth factor in an unknown organ through an Esr1-dependent mechanism that impacts uterine growth and adenogenesis.
Recently, global ablation of KiSS-1 metastasis suppressor (Kiss1) or its receptor (Kiss1r) in mice was also observed to impair uterine growth and decreased gland number by 50% at P21 (116). Although circulating levels of estrogen were not different, both adult Kiss1- and Kiss1r-null mice had smaller uteri with few or no Foxa2-positive glands (116). Estrogen replacement of Kiss1-null mice from 3 to 4 weeks of age for 5 weeks restored uterine growth, but it only partially rescued adenogenesis. Similarly, reexpression of Kiss1r in the hypothalamus of adult Kiss1-null mice restored uterine growth, but it only partially rescued gland development based on Foxa2-positive gland numbers. Alterations in ovarian inhibin (Inhba) and follistatin gene expression were observed in Kiss1r-repleted Kiss1-null mice. Collectively, these recent studies support the idea that uterine growth and gland maintenance after P21 is complex and involves actions of extrinsic ovarian-derived factors, such as estrogen and activin A, as well as peripheral-derived Kiss1-dependent factors from other organs.
Mammary gland and the lactocrine hypothesis
Lactation, the secretion of milk by the mammary glands, is a defining characteristic of mammals, and maternal milk contains a complex array of bioactive factors (117, 118). Findings in the pig strongly support that bioactive factors communicated from mother to nursing offspring in first milk (colostrum) may provide a vital source of extraovarian, uterotrophic support (118, 119). The term lactocrine refers to a mechanism by which milk-borne bioactive factors are communicated from mother to offspring in colostrum during nursing (117, 120, 121).
In the pig, uterine glands are absent or rudimentary at birth (12). Between birth and P3, nascent GE cells differentiate from LE and begin to proliferate rapidly, forming uterine glands (86, 122). This neonatal period coincides with the time during early lactation when concentrations of bioactive factors in colostrum are highest (118, 119, 123). Within 48 hours after birth, macromolecular components of colostrum are no longer able to diffuse readily across the intestinal epithelium (119, 124). Lactocrine effects on neonatal porcine uterine development occur immediately after birth upon first ingestion of colostrum. A single feeding of colostrum at birth increased endometrial cell proliferation at 12 hours postnatally. In the same regard, nursing for 12 hours from birth supported the establishment of the uterine developmental program as reflected by patterns of uterine cell proliferation and expression of morphoregulatory genes (125). Imposition of a lactocrine-null state in the neonatal gilt by feeding milk replacer for 2 days from birth decreased uterine gland development and endometrial thickness on P14 (126). Consistently, both glandular ESR1 expression and cell proliferation were reduced on P14 in uterine tissues obtained from lactocrine-null gilts (126). Further studies established that lactocrine support from birth alters the postnatal uterine developmental program and trajectory of uterine development in the neonatal pig and contributes to the programming of endometrial tissues necessary to support optimal embryotrophic function of the uterus into adulthood (118, 119, 127).
Progesterone as an endocrine disruptor
The developing and adult FRT is highly sensitive to synthetic chemicals, in particular, those mimicking hormones utilizing nuclear receptors. Endocrine-disrupting compounds [see Ref. (128)] are either natural or synthetic exogenous compounds that interfere with the physiology of normal endocrine-regulated events, such as reproduction and growth (129), because they are agonists and antagonists of nuclear hormone receptors. Although ovarian steroids and their receptors (Esr1, Pgr) are not required for fetal FRT organogenesis or initial neonatal uterine development, their receptors are expressed in the prenatal and postnatal uterus during critical developmental windows. Thus, the uteri of humans (130), rodents (131–135), cattle (136), pigs (86, 137–139), and sheep (95, 140) are particularly vulnerable to developmentally disruptive effects of natural or synthetic endocrine-disrupting compounds.
Studies in rodents (28, 107) and sheep (31, 109) established that onset of adenogenesis in the neonatal uterus occurred independently of a requirement for ovarian support or steroid hormones and that progestins could suppress uterine epithelial cell proliferation. Consequently, it was hypothesized that birth provides an endocrine cue for the initiation of uterine gland genesis (109). Subsequently, exposure of newborn sheep to norgestomet, a nonmetabolizable and potent synthetic form of progesterone, from birth was found to inhibit uterine adenogenesis (109). Removal of norgestomet on P13 permitted glands to develop by P26, although those glands were underdeveloped and histologically abnormal. This original observation served as the foundation for the idea that prolonged exposure of neonatal ewes to progestins during the critical period of adenogenesis would permanently inhibit uterine gland differentiation (11). Subsequently, exposure of neonatal ewes to norgestomet from birth to 8 weeks of life was discovered as a method to permanently inhibit postnatal differentiation of uterine glands, thereby creating a uterine gland knockout (UGKO) phenotype in adults (141–143). In neonatal sheep, norgestomet inhibition of adenogenesis involved inhibition of LE proliferation and expression of ESR1 and FGFR2 (109, 141). Adult UGKO ewes exhibited complete infertility due to recurrent early pregnancy loss stemming from defects in blastocyst survival and growth (1).
In neonatal mice, transient exposure to progesterone from P2 to P10 permanently inhibited uterine adenogenesis and produced a UGKO phenotype in the adult (2, 144). Progesterone treatment decreased uterine LE proliferation and increased stromal cell proliferation (91, 144, 145). The antiproliferative actions of progesterone on the LE, some of which serve as GE progenitors, may be the underlying cause of failure in endometrial adenogenesis (24). Increased stromal cell proliferation could also disrupt stromal–epithelial crosstalk necessary for GE differentiation (9, 26, 146, 147). In the adult mouse uterus, Indian hedgehog (Ihh) is a progesterone-upregulated gene expressed in the LE and GE (144, 148, 149). Ihh acts in a paracrine manner through smoothened (SMO) in the stroma to regulate LE cell proliferation, and overexpression of Smo using Pgr-Cre mice caused defects in adenogenesis (150, 151). Interestingly, the antiadenogenic effects of progesterone are not observed in Ihh-null mice or mice lacking Pgr in the uterine epithelium (152). Similar to UGKO sheep, progesterone-induced UGKO (PUGKO) mice are infertile and exhibit recurrent early pregnancy loss due to failure in embryo implantation (144, 153). Studies with UGKO sheep and mice established that uterine glands and, by inference, their secretions and products are primary determinants of pregnancy success.
Functional Roles of Uterine Glands
Uterine glands directly synthesize and secrete or selectively transport from serum transudate a wide variety of substances, collectively termed histotroph, into the lumen of the uterus (4). Histotroph is complex and comprised of many different substances, including ions, sugars (glucose and fructose), amino acids, extracellular vesicles (exosomes and microvesicles), lipids, and proteins. Recent studies of UGKO sheep and mice established that uterine glands and, by inference, their products and secretions are essential for pregnancy and have biological roles in conceptus survival and growth, uterine receptivity, embryo implantation, stromal cell decidualization, and placental development (Figs. 4 and 5) (154).
Figure 4.
Uterine glands secrete factors that impact pregnancy establishment in the mouse. In response to the nidatory surge in ovarian estrogen on day 4 of pregnancy, LIF is secreted from FOXA2-positive uterine glands, causing HBEGF expression for trophoblast attachment and adhesion to the LE. Following attachment, unknown gland-derived factors are involved in coordinating the removal of the LE (entosis) within the implantation chamber, allowing for direct contact between the trophoblast and decidualizing stromal cells (PTGS2). Uterine glands are involved in secondary stromal cell decidualization (SDZ), but the identification of factors involved in mediating those processes requires the establishment of new in vivo and in vitro model systems.
Figure 5.
Hypothesis on the interrelationships of the ovarian corpus luteum, conceptus trophoblast, uterine glands, and decidual cells during early pregnancy in humans. See text for detailed description of hypotheses and supporting data. [Adapted from Burton GJ, Jauniaux E, Charnock-Jones DS. Human early placental development: potential roles of the endometrial glands. Placenta. 2007;28(Suppl A):S64–S69. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.]
UGKO models
Sheep
The uteri of adult UGKO ewes are histoarchitecturally normal except for the lack of GE and reduced LE (142). Notably, development and function of the brain (hypothalamus and pituitary), ovary, and other FRT structures (oviducts, cervix, and vagina) were not altered in UGKO ewes (142, 155). UGKO ewes exhibit complete infertility due to recurrent pregnancy loss (142, 143, 156). Morphologically normal blastocysts were present in UGKO ewes after mating on gestational day (GD) 9, but conceptuses were absent or severely growth retarded when assessed on GD12 or GD14. Moreover, transfer of blastocysts from normal ewes was unable to rescue pregnancy in the UGKO ewes. Thus, failure of conceptus elongation in UGKO ewes was attributed to the absence of specific, embryotrophic secretions that emanate primarily from the glands (1, 143).
Embryotrophic factors produced by the uterine glands that are required for conceptus survival and elongation have not been defined in sheep. Progesterone drives changes in expression of genes by the endometrial epithelium (LE and GE) that modulate transport of ions, amino acids, glucose, and lipids from serum and produce proteins, extracellular vesicles, and other bioactive substances (prostaglandins and cortisol) (3, 157–161). Arginine is one of the only components of histotroph demonstrated in vivo to be functionally important for blastocyst growth in sheep (162).
Mice
UGKO mice can be created by exposure of neonatal mice to progesterone from P2 to P10 (144, 145, 163) or conditional deletion of Foxa2 using Pgr-Cre mice (67–70).
Except for the uterus, the FRTs of PUGKO and Pgr-Cre:Foxa2 cKO mice were histoarchitecturally indistinguishable from those of wild-type mice. Both PUGKO and Pgr-Cre:Foxa2 cKO mice cycled and mated normally but were infertile due to an embryo implantation defect. Histological assessment of their uteri found hatched blastocysts apposed to an intact LE without evidence of embryo implantation or the onset of stromal cell decidualization (153, 163). Expression of leukemia inhibitory factor (Lif), a critical implantation factor of GE origin (164), was absent in the uteri of UGKO mice, whereas steroid hormone receptors (Esr1, Pgr) and their regulated genes were not different with the exception of Lif. Of note, Lif-null mice are also infertile due to defective embryo implantation (164). Blastocysts from PUGKO mice could be successfully transferred into the uterus of wild-type recipients, where they implanted and established pregnancy (153). Thus, the infertility observed in UGKO mice was attributed to faulty uterine receptivity resulting from the absence of LIF and perhaps other specific uterine gland–derived products.
As in domestic animals, the essential factors produced by the uterine glands that impact pregnancy establishment in mice are not known with the exception of LIF. Sequential effects of ovarian and progesterone alter expression of genes in the endometrial epithelium (LE and GE), but the biological roles of most of those genes have not been determined (65, 69, 165). Moreover, few studies have characterized components of histotroph in the uterine lumen of mice. Carbohydrates and amino acids in the uterine lumen were initially profiled only from mice at estrus (166). Recently, glucose, amino acids, and proteins were profiled in the uterine lumen of pseudopregnant mice during the acquisition of uterine receptivity (153). Different from domestic animals and humans, dynamic changes in those histotroph components were not observed. Surprisingly, many proteins and most amino acids were more abundant in uterine luminal fluid from PUGKO than wild-type mice, indicating that uterine glands have a primarily biological role in homeostasis of the uterine lumen (153). Of note, LIF and serine peptidase inhibitor Kazal type 1 (Spink1; also known as Spink3), which are GE-specific gene products (167), were not identified in the uterine lumen of wild-type mice. That study supports the idea that the polarized GE can secrete proteins and other substances in a basolateral direction that primarily act in a paracrine manner on the stroma, immune cells, vascular endothelium, and basal aspect of the LE. In contrast, apical secretions of GE cells would primarily enter the uterine lumen and impact embryo and placental development.
Biological roles of uterine glands in pregnancy establishment: lessons from Foxa2 cKO mice
Uterine receptivity is defined as a temporally unique sequence of factors that make the endometrium receptive to embryo implantation and are mainly regulated by ovarian steroid hormones estrogen and progesterone (168, 169). In mice, the uterus becomes receptive on day 4 of pregnancy (day 1 represents observation of a postcoital vaginal plug), whereas by the afternoon of day 5, it spontaneously becomes refractory to blastocyst implantation (170–173). When synchrony between an implantation-competent blastocyst and receptive endometrium is achieved, blastocyst implantation commences (173, 174). The outer trophectoderm (TE) cells of the blastocyst then attach and adhere to the LE. Penetration into the stroma involves removal of the LE and migration of the TE. Implantation triggers robust stromal cell decidualization, which is critical for pregnancy success in mice and humans (175–177).
In its broadest sense, decidualization can be viewed as the postovulatory process of endometrial remodeling in preparation for pregnancy that includes coordinated proliferation and differentiation of endometrial stromal cells into large epithelioid decidual cells, secretory transformation of the uterine glands, influx of specialized uterine natural killer cells, and vascular remodeling (169, 175, 178–182). Many of the cellular and genetic changes in decidualizing stromal cells are conserved between mice and humans (176, 183). In mice, initiation of embryo attachment reaction, occurring near midnight on GD4, is followed by extensive stromal cell proliferation surrounding the implanting blastocyst that is evident by the morning of GD5. Between GD5 and GD6, stromal cells, adjacent to the implanted blastocyst in the antimesometrial area of the uterus, cease proliferating and undergo differentiation, forming the primary decidual zone (PDZ), an area that is avascular and epithelioid (179). Stromal cells adjacent to the PDZ continue to proliferate and differentiate to form the secondary decidual zone (SDZ). In humans, decidualization commences during the mid-secretory phase (5 to 7 days after ovulation) in both nonpregnant and pregnant women and progresses significantly in the area beneath and surrounding the embryo implantation site (183).
Blastocyst activation
Blastocyst activation is the process by which the blastocysts acquire implantation competency and can attach to receptive uterine LE (184). Amino acid and glucose transport into the uterine lumen is hypothesized to be essential for blastocyst activation and implantation based on in vitro studies. Both leucine and arginine are required in culture media for blastocyst activation and trophoblast motility in the preimplantation mouse embryo (184–186). Precise regulation of glucose within the uterine lumen is likely an essential component for embryo activation and implantation. Mouse and human embryos require glucose in vitro, but increased glucose concentration can result in developmental delays and increased embryo death (187–191). Transporters for glucose and amino acids are expressed in the uterine glands and may impact trophoblast activation and motility that are necessary for embryo implantation (153, 185, 192). In species exhibiting embryonic diapause (skunks, mice, bears), uterine glands are thought to modulate embryo quiescence and reactivation by altering bioactive substances, such as selected amino acids and polyamines, in the uterine lumen (193, 194).
Uterine receptivity and implantation
Uterine glands and their secretions have long been implicated in uterine receptivity and blastocyst implantation in mice and humans (154, 195–198). Studies on LIF in mice provided the first unequivocal evidence that uterine glands secrete a factor required for uterine receptivity and blastocyst implantation (199). Lif is expressed explicitly on GD4 by the uterine GE in response to the “nidatory” surge of estrogen from the ovary (164, 200, 201). Lif-null mice are infertile owing to defects in embryo implantation, but IP injections of recombinant mouse LIF initiated embryo implantation and rescued pregnancy in Lif-null mice (164). Moreover, conditional uterine knockout of Gp130 and Stat3, downstream mediators of LIF signaling, results in implantation failure phenocopying that is seen in Lif-null mice (202). Implantation defects in other null mutant (Lef1) and conditional mutant mice (Ctnnb1, Foxa2, Lgr4, Wnt4, Wnt7a) lacking uterine glands are also attributed to diminished or absent Lif expression (35, 36, 38, 41, 57).
Recently, Foxa2 was conditionally deleted in the epithelium of the adult uterus after puberty using the new and very useful lactotransferrin (Ltf)-iCre mouse model (203). In both gland-containing Ltf-iCre:Foxa2 cKO and glandless Pgr-Cre:Foxa2 cKO mouse models, blastocysts failed to attach and adhere to the LE and initiate stromal cell decidualization for pregnancy establishment. Steroid receptors and most established hormone-regulated uterine receptivity genes were not different in the Foxa2 cKO and wild-type mice (67, 68, 153, 163). As expected, uteri of glandless Pgr-Cre:Foxa2 cKO mice lacked Lif expression on GD4 (67, 68, 153, 163). Surprisingly, uteri of Ltf-iCre:Foxa2 cKO mice also lacked Lif expression despite having uterine glands (68). Both Foxa2 cKO mouse models phenocopy Lif-null and PUGKO mice in that they exhibited defects in blastocyst implantation. Studies of Ltf-iCre:Foxa2 cKO mice established that Foxa2 regulates the ability of estrogen and Esr1 to induce Lif and perhaps other GE genes (68, 70). Both FOXA1 and FOXA2 influence ESR1 transcriptional activity in other organs and cancer cells (204, 205).
Remarkably, IP injections of LIF on GD4 was able to rescue implantation in both gland-containing Ltf-iCre:Foxa2 cKO and glandless Pgr-Cre:Foxa2 cKO mice (68, 70). Heparin-binding EGF (Hbegf) induction in the LE adjacent to the blastocyst is an early molecular marker of the attachment reaction in mice (206). Hbegf expression was not observed in the LE adjacent to the blastocysts of both types of Foxa2 cKO mice on the night of GD4; however, LIF repletion was sufficient to trigger blastocyst attachment to the LE, induction of Hbegf expression, and blastocyst implantation (70). These studies with Foxa2 cKO mice and others firmly establish that LIF is a critical factor derived and secreted by the GE that acts on the LE to establish uterine receptivity and permit activated blastocysts to initiate TE attachment and implantation in mice.
In rodents, implantation crypt formation is essential for pregnancy success (54, 202, 207). The crypts form in the gland-containing antimesometrial area of the uterus on GD4, and blastocysts enter those crypts before the onset of the attachment reaction. Implantation crypt formation is independent of the preimplantation surge in estrogen from the ovary, as it also occurs in a delayed implantation mouse model (203). Several mutant mouse lines (Msx1/2, Wnt5a, Vangl2) exhibit aberrant crypt formation resulting in increased embryo resorption (54, 202, 207). Histological studies of Pgr-Cre:Foxa2 cKO mice established that implantation crypt formation and localization of blastocysts within those crypts were not different from wild-type mice (70).
New 3D visualization studies revealed that epithelial evaginations forming implantation chambers (crypts) consistently arise with preexisting glands, suggesting direct access of glands to embryos and decidual cells within the chamber (20). While the lobular domains of the glands become more developed, the ductal regions continue to elongate and progressively stretch following embryo implantation. Thus, glands remain in the implantation site surrounding the embryo during implantation, decidualization, and pregnancy establishment. Notably, the mechanisms allowing for the selective removal of the LE but not the GE by the TE during early implantation have not been investigated.
Stromal cell decidualization
The concept that uterine glands secrete paracrine-acting factors into the stroma to promote decidualization is relatively new (196). Studies of Spink1, a gland-specific gene in the uterus, support this concept (167). Although Spink1 mRNA is present only in the GE of the mouse uterus, Spink1 protein was detected in the LE and decidual cells as well as glands of the pregnant mouse uterus. Furthermore, Lif, Spink1, and other GE-specific proteins were not identified in a proteomic analysis of the uterine lumen of mice (153). These studies support the idea that vectorial secretion of proteins in a basolateral direction by the polarized GE has paracrine effects on other cell types within the endometrium, including the stroma, immune cells, and LE (Figs. 4 and 5).
The first evidence that endometrial glands may impact stromal cell decidualization originated from studies of deciduoma formation in glandless mice (67). An artificial model of decidualization can be employed in mice that involves ovariectomy, hormone replacement, and intrauterine administration of oil as a deciduogenic stimulus (208). Using that artificial model, PUGKO mice exhibited a distinct lack of uterine stromal cell decidualization termed a deciduoma (163). Similarly, mice with conditional ablation of Foxa2, Lgr4, or Wnt4 have a uterus with much reduced or absent glands and also exhibit defects in blastocyst implantation and stromal cell decidualization (35, 57, 67, 68).
Morphological and mechanistic studies of UGKO mice (PUGKO and Pgr-Cre:Foxa2 cKO) support the concept that uterine glands secrete factors that impact stromal cell decidualization. In UGKO mice, there is no evidence of LE cell removal and stromal cell decidualization adjacent to the blastocyst (67, 68, 70, 153, 163). In LIF-replaced Foxa2 cKO mice, GD6 implantation sites appeared normal based on morphology (decidual swellings), histology, cell proliferation (Ki67), and upregulation of prostaglandin-endoperoxide synthase 2 (Ptgs2), a molecular marker of PDZ formation (68, 70). However, by GD7, defects in embryo development and decidual regression were evident in LIF-replaced glandless mice, with full embryo loss and resorption by GD10 (68). Transcriptome analysis of GD6 implantation sites revealed numerous genes and pathways altered in the uterus of control as compared with LIF-replaced glandless Pgr-Cre:Foxa2 cKO mice. Interestingly, many known decidualization-related genes are increased in implantation sites of glandless Pgr-Cre:Foxa2 cKO mouse uteri (Bmp2, Cdh1, Cebpb, Ptx3, Wnt4) (70), which may signify premature stromal cell differentiation into decidual cells (181). The increased expression of genes crucial to decidualization on GD6 and persistence of stromal proliferation on GD7 suggest perturbed decidual progression and premature decidual senescence in Pgr-Cre:Foxa2 cKO mice. These findings support the idea that uterine glands produce paracrine-acting factors that govern stromal cell decidualization by modulating proliferation, differentiation, and/or polyploidization (177) (Figs. 4 and 5). The concept of gland-derived factors influencing decidualization is novel and supported by evidence that LIF enhanced mouse and human endometrial stromal cell decidualization in vitro (209).
In LIF-replaced gland-containing Ltf-iCre:Foxa2 cKO mice, stromal cell decidualization progresses with the formation of a functional SDZ and placenta based on histology (68). There is no difference in implantation site number in LIF-replaced gland-containing Ltf-iCre:Foxa2 cKO mice and control mice on either GD6 or GD10 or number of live pups at term. Although no overt histological differences were observed in the decidua and placenta, the expression of several genes involved in decidualization (Alpl, Bmp2, Bmp8a, Fstl1, Prl8a2, Wnt4) were lower in the GD6 and GD10 implantation sites from LIF-replaced gland-containing Ltf-iCre:Foxa2 cKO mice as compared with wild-type control mice (68). A recent intriguing study found marked differences in the transcriptome of the GD15 placenta from LIF-replaced gland-containing Ltf-iCre:Foxa2 cKO mice compared with wild-type mice (210). That study provides more evidence that glands impact stromal cell decidualization with reciprocal effects on the development of the placenta.
Collectively, studies of uterine Foxa2 cKO mice support the ideas that: (i) uterine glands and, by inference, their secretions and products are unequivocally required for implantation, stromal cell decidualization, and pregnancy establishment; and (ii) Foxa2-dependent products of the uterine glands influence development of the placenta likely via effects on stromal cell decidualization. Of note, functional Foxa2-positive glands remain in the uterus during pregnancy and surround the implantation site during pregnancy establishment in mice (20, 70). Molecular analyses revealed that Foxa2 regulates a large number of genes in the uterine glands that are involved in steroid biosynthesis, hedgehog signaling, cell adhesion, and biosynthesis of unsaturated fatty acids as well as encodes secreted and transport proteins (65). However, the impacts of most Foxa2-regulated and GE-expressed and GE-specific genes on uterine function and pregnancy remain unknown.
Uterine glands and pregnancy establishment in humans
The human endometrium is lined by a simple columnar LE and contains numerous coiled tubular glands that radiate through the endometrial stroma toward the myometrium (197). Adult human and primate endometria are divided into two functional layers, the upper stratum functionalis containing glands surrounded by loose stroma, and the lower stratum basalis containing gland bodies and dense stroma. The human endometrium has a high density of uterine glands, ∼15 gland openings per square millimeter, and an increase in gland area is observed in the secretory phase compared with the proliferative phase (211, 212).
As in other species, the LE and GE of the human endometrium have distinct molecular signatures depending on the phase of the menstrual cycle (213). Components of histotroph in the uterine lumen of humans is similar to animals and includes ions, carbohydrates (glucose), amino acids, many different kinds of proteins, lipids, and extracellular vesicles (214–225). The GE transcriptome, secretome, and metabolome represent a significant gap in our knowledge of uterine gland biology.
For many decades, secretions of uterine glands were hypothesized to play an essential role in sustaining the conceptus prior to implantation (224, 225). However, their role in postimplantation conceptus growth and development was largely ignored until recent transformational studies of the early human placenta (154, 211, 226, 227). Implantation of the blastocyst begins about day 7 and is complete by days 10 to 12 after conception (227–229). Initially, the blastocyst TE attaches to the uterine LE between openings of the uterine glands (230). As the TE of the blastocyst begins to appose, attach, and adhere to the LE, the cytotrophoblast (CTB) begins to differentiate and form a syncytiotrophoblast (STB) that then penetrates between the LE cells into the stroma. The implanted conceptus becomes encapsulated within the superficial endometrium via a combination of invasion and proliferation of the surrounding decidualizing stromal cells (154, 227). By the time implantation is complete, the chorionic sac is surrounded by a mantle of STB in which spaces representing the forerunners of the intervillous space (lacunae) are already present. As the STB enlarges, it erodes into the necks of the glands. Consequently, connections between the lumens of glands and the developing intervillous spaces of the placenta can be observed as early as day 17 postfertilization (231) and persist throughout the first trimester (211). Indeed, uterine glands remain highly active during the first trimester of pregnancy and deliver their secretions into the developing intervillous spaces of the placenta (211, 222, 232, 233). In fact, the uterine glands near the implanting chorionic tissue of the conceptus become hypersecretory (234), which is termed the Arias-Stella reaction (235, 236).
The first connection between uterine glands and the implanting blastocyst can be observed by two-dimensional histology at the time of implantation in humans (237). A putative subpopulation of extravillous trophoblasts, termed endoglandular trophoblasts, appear to invade uterine glands at the margin of the developing placenta during the first trimester (232, 238). Further evidence for endoglandular trophoblasts has been generated by histological assessment of first trimester placenta and placental bed specimens and an in vitro model of early placenta/decidua confrontation coculture (232, 238, 239). Quantitative analysis of trophoblast invasion into vessels and glands of the placental bed revealed significantly more replacement of epithelial cells in glands compared with endothelial cells in blood vessels during the first trimester of pregnancy. It is tempting to speculate that paracrine factors, secreted by the GE and trophoblasts, are responsible for migration of trophoblast cells and the disintegration of the GE (232). The evidence for an endoglandular trophoblast subtype in the early placenta is contentious, as recent single-cell sequence data from first trimester placenta and decidua did not identify a unique transcriptomic signature for those cells (240).
The importance of uterine glands and histotrophic nutrition during the first trimester of pregnancy was only realized once it was recognized and documented that the maternal arterial circulation to the placenta is not fully established until 10 to 12 weeks of gestation (8 to 10 weeks postfertilization) (241–243). During early pregnancy, the spiral arteries of the human uterus are yet to penetrate the superficial third of the functionalis, and the conceptus has to appreciably enlarge before it can contact the tips of the spiral arteries and break into and plug them using endovascular trophoblast cells. Thus, the end of the first trimester represents a change from histotrophic to hemotrophic nutrition when the plugs of endovascular trophoblast dissipate and allow for directed blood flow into the intervillous spaces of the placenta (211, 226). Before that time, the intervillous space is likely filled with secretions derived primarily from the uterine glands (234). In essence, the relationship between decidual uterine glands and conceptus is equivalent in humans and domestic animals, except that uterine gland secretions are intraplacental rather than intraluminal (227).
The uterine glands represent an important source of nutrients for the human conceptus throughout the first trimester (154, 222, 227). Indeed, adequate nutrition of the blastocyst/conceptus has long-term implications for the growth of the fetus and health of the adult (244, 245). Although amino acids and sugars are crucial for early embryogenesis and conceptus growth in other species (246), few studies have examined their transport systems in human endometrium and, particularly, the uterine glands. Evidence that the glands may act as a source of nutrition for the human embryo is provided by the observation that the STBs covering the surfaces of villi facing the endometrium contain accumulations of glycogen (211). These accumulations are highest close to the maternal–fetal interface, suggesting a concentration-dependent uptake by the trophoblast. The first-trimester STB also phagocytizes glycoproteins from the glands such as progestagen-associated endometrial protein (PAEP; also known as glycodelin) (211), which is expressed in the GE but not in placental tissues (247). Of note, little information is available on the genes expressed by, and secretions produced by, the uterine glands, particularly during the first trimester.
Besides providing a source of nutrients, the uterine glands may play a more active role in regulating placental development of the human conceptus through the production of growth factors (Fig. 5). A variety of growth factors have been identified within the GE, including EGF, vascular endothelial growth factor, and LIF, and receptors for these factors are present on the placenta during the first trimester (222). Growth factors, such as LIF and FGF, are critical for the maintenance of trophoblast stem cells (248). Furthermore, EGF treatment of villi from early gestation stimulated CTB proliferation and enhanced secretion of chorionic gonadotropin (CG) and CSH1 (249). The proliferation of CTB is essential, because it is required for: (i) establishment of villous trees and maintenance of the STB layer that performs nutrient exchange and secretes endocrine factors such as CG and CSH1; (ii) generating a complete CTB shell that protects the conceptus during early pregnancy; and (iii) providing a sufficient supply of extravillous trophoblast cells that are pivotal in remodeling the spiral arteries. Thus, uterine gland secretion of growth factors into the intervillous spaces of the placenta may create a microenvironment that stimulates trophoblast cell proliferation and differentiation necessary for optimal growth and development of the conceptus (Fig. 5).
“The uterine glands represent an important source of nutrients for the human conceptus throughout the first trimester.”
Hormonal regulation of uterine gland function
The idea that factors from the ovary and conceptus can influence uterine gland development and function stems from work in domestic animals (3, 250) and rabbits (251). In sheep, intrauterine infusions of placental hormones, interferon-τ and then either CSH1 (also known as placental lactogen) or GH, into the progestinized uterus elicited gland hypertrophy and increased their secretory function (252–254).
An equivalent mechanism is likely present in the human uterus (154, 196, 227) (Fig. 5). Initially, progesterone downregulates expression of the PGR that results in substantial changes in and induction of gene expression in the uterine glands referred to as secretory transformation (255). However, the PGR continues to be expressed by the decidual cells, and progesterone effects via PGR are unequivocally required for stromal cell decidualization and function. One of the first products of the conceptus is the pregnancy recognition signal CG produced by the STB that acts in an endocrine manner via its receptor (LHCGR) in the corpus luteum to maintain progesterone secretion (256), as well as in a paracrine manner on GE cells to increase their secretory function (257, 258). Moreover, treatment of isolated GE cells with highly purified CG resulted in a time- and dose-dependent increase in levels of PTGS2 expression and consequent secretion of prostaglandin E2 (PGE2) (256), which potentiates stromal cell decidualization. In addition to CG, lactogenic hormones from the placenta (CSH1 from STB) and decidua (PRL) act on the uterine glands. PRL is a major progesterone-regulated secretory product of decidualized stromal cells, and the PRLR is abundant in the uterine glands during the secretory phase and early pregnancy (259). Thus, lactogenic hormones are proposed to stimulate uterine gland secretory functions in concert with CG (Fig. 5). In turn, the uterine gland secretions and products regulate development and/or function of the placenta via effects on the CTB and STB. In this way, the conceptus has a direct impact on the supply of nutrients and other factors it receives from the mother (154, 227).
The concept of gland-derived factors influencing decidualization is relatively new, but it was first supported by evidence that LIF enhanced decidualization of human and mouse stromal cells in vitro (209). In women, the LE and GE maximally express LIF during the mid-secretory phase of the menstrual cycle (260), suggesting that glands may influence stromal cell decidualization prior to implantation that occurs in women but not in rodents. Peptide hormones and prostanoids implicated in promoting decidualization of stromal cells in the human include CG, CRH, relaxin, and PGE2, as they all increased intracellular levels of cAMP that stimulates stromal cell decidualization in vitro (261). Indeed, several cytokines and growth factors (IL-11, relaxin, PGE2, activin A, CRH, and LIF) progress or enhance in vitro progesterone-induced decidualization of endometrial stromal cells from humans and/or mice (209, 262). Determination of factors produced by uterine glands during the first trimester and their potential paracrine actions on the stroma, decidua, and placenta is an important area for future studies in humans.
Perspectives on the Future
Developmental biology of uterine glands
Development of the GE of the uterus involves terminal differentiation of epithelial cells derived from multipotent cells within the LE. This process is undoubtedly mediated by transcription factors and epigenetic modifications that orchestrate the accompanying changes in gene expression and, in turn, create heritable cellular memories characteristic of both specific lineages and cell types. FOXA2 is a GE-specific transcription factor in humans and all studied animals that is critical for GE specification, differentiation, and development in mice (67, 69). Understanding how Foxa2 is activated only in nascent GE and repressed in the LE of the developing and adult uterus is essential to understand GE identity. Studies of the developing endoderm in the fetus suggest a novel and unexpected role for DNA methylation in the activation of Foxa2 gene expression during differentiation (263). However, little information is available regarding the precise molecular mechanisms that control Foxa2 gene expression (264) as well as the genes that Foxa2 regulates in the developing uterus (69).
Although several mouse models are available to conditionally delete genes specifically in both the LE and GE in the neonatal and adult mouse uterus, there are no uterine GE-specific Cre mice that can be used to conditionally delete genes and determine their function in the developing or adult uterus. The lack of such mouse models hampers understanding of uterine gland developmental biology, particularly because studies of this type are practically impossible in humans.
Functional role of uterine glands in pregnancy
Determination of factors produced by uterine glands and their potential paracrine actions on cells of the stroma, decidua, and placenta is an important area for future studies in humans. The inability to obtain samples of implantation sites during the first trimester of pregnancy poses a significant challenge to the study of uterine gland biology. Therefore, continued discoveries in this area require rodent models as well as in vitro culture systems. Fortuitously, human endometrial biopsies can be used to generate 3D organoid cultures of glands that can be expanded long-term, are genetically stable, and differentiate following treatment with reproductive hormones (265, 266). Following exposure to pregnancy signals, endometrial gland organoids develop characteristics of the early pregnant endometrium. Indeed, single GE cells can generate organoids from either normal or diseased endometrium (265). Thus, they provide an important foundation to study the physiology of early gestation, common diseases, such as endometrial cancer and endometriosis, and for toxicology and drug discovery studies. One could envision adding additional components of the endometrium (stroma, immune cells, vascular) that are important for generating a fully functional organ-on-a-chip model of the human endometrium (267, 268).
Medical Horizons and Translational Aspects
Reproductive failure and fertility diagnostics
The substances in uterine histotroph are presumed to be primarily from the uterine glands and important mediators of uterine receptivity, blastocyst implantation, stromal cell decidualization, and placental growth (154, 173, 223, 227). Deficient glandular activity, usually described as a “secretory phase defect,” is hypothesized to be a significant underlying cause of early pregnancy failure in humans (154, 269). Recent proteomic studies found that proteins in the uterine lumen of fertile women change during the menstrual cycle and are altered in the uterine lumen of fertile as compared with infertile women (214, 270, 271). Thus, analysis of the uterine lumen offers a minimally invasive means of studying uterine secretions and function in women and can be conducted before embryo transfer in an assisted reproduction cycle without negatively affecting implantation rates (271, 272). Indeed, this approach was recently used to determine that IL-1β and TNF were key predictive markers of implantation in women undergoing in vitro fertilization and embryo transfer (214). However, an expanded set of biomarkers is expected to provide the most sensitive and accurate means for assessing uterine receptivity for conceptus implantation (224, 225). Those biomarkers could be based on secretions of the uterine glands that are present in the uterine lumen or assessed in an endometrial biopsy (273, 274). Thus, determination of the mid-secretory phase GE transcriptome, secretome, and metabolome is important.
Pregnancy complications
It is increasingly clear that histotroph from the uterine glands is essential for blastocyst survival, growth, and implantation in humans (224, 225) and may also be involved in pregnancy loss and complications such as miscarriage, preeclampsia, and fetal growth retardation (154, 226). Defective development of uterine glands during the cycle as well as deficient secretory activity have been speculated to be causes of early pregnancy failure in humans; however, there is little but circumstantial evidence to support that hypothesis. Low PAEP levels in uterine flushes are correlated with recurrent miscarriage, which could result from deficient gland development or function (275). Miscarriage and preeclampsia may result from insufficient glandular activity causing an incomplete cytotrophoblastic shell, inadequate trophoblast proliferation, or abnormal decidual function. Moreover, defects in stromal cell decidualization can cause pregnancy loss due to miscarriage (183) and have been recently implicated in the origin of later pregnancy complications, including preeclampsia and fetal growth retardation (276). Thus, a more comprehensive understanding of the biological roles of uterine glands in blastocyst/conceptus growth and implantation, uterine receptivity, and uterine decidualization is needed to generate new knowledge essential for understanding implantation failure and pregnancy loss and to improve pregnancy success.
Regenerative medicine
Uterine gland biology is also crucial for regenerative medicine therapies aimed at organ replacement and stem cell therapies to treat infertility and pregnancy loss as well as disease in women (277). Asherman syndrome is characterized by intrauterine adhesions (synechiae) or fibrosis that results as a consequence of damage to the basal layer of the endometrium (278). This disease often leads to hypomenorrhea or amenorrhea, infertility or recurrent pregnancy loss, and preterm premature rupture of membranes, placental abruption, and malpresentation. Asherman syndrome occurs most commonly as a result of trauma or infection, particularly after pregnancy when estradiol levels are low. It occurs in up to 25% of patients treated with dilatation and curettage postpartum. There is substantial evidence in the literature that adult endometrial tissue contains epithelial progenitor cells and mesenchymal/stromal cells (279, 280). These cells could be the target of specific therapy to regenerate the endometrial tissue in cases of a dysfunctional or atrophic endometrium.
Conclusion
Uterine glands and their secretions have important biological roles in mammalian pregnancy. Some of the biological pathways involved in uterine gland development and function have been identified through in vivo studies of mice, pigs, and sheep; however, significant gaps remain in our knowledge of the hormonal, cellular, and molecular mechanisms regulating uterine gland development, programming, and adult function. Future research in this area will undoubtedly involve new techniques in 3D visualization of uterine histoarchitecture (19, 20) and in vitro studies of uterine gland organoids (265, 266). A comprehensive understanding of the biological role of uterine glands and their secretions in blastocyst/conceptus growth and implantation, uterine receptivity, and conceptus/placental development and function throughout pregnancy is needed. Efforts to advance understanding in this domain will generate new knowledge essential for understanding pregnancy loss and development of strategies to improve pregnancy outcomes and reproductive efficiency as well maternal and fetal health.
Acknowledgments
We thank the present and past members of our laboratories for their scientific contributions.
Financial Support: This work was supported by Grants R01 HD096266 and R21 HD087589 from the National Institute of Child Health and Human Development of the National Institutes of Health (to T.E.S.) and by the Intramural Research Program of the National Institute of Environmental Health Sciences Project Z1AES103311 (to F.J.D.).
Disclosure Summary: The authors have nothing to disclose.
Glossary
Abbreviations:
- 3D
three-dimensional
- CG
chorionic gonadotropin
- cKO
conditional knockout
- CSH1
chorionic somatomammotropin hormone 1
- CTB
cytotrophoblast
- CTNNB1
catenin (cadherin-associated protein) β1
- DLX
distal-less homeobox
- EGF
epidermal growth factor
- ESR1
estrogen receptor α
- FGF
fibroblast growth factor
- FOX
forkhead box
- FRT
female reproductive tract
- FZD
frizzled
- GD
gestational day
- GE
glandular epithelium
- HBEGF
heparin-binding EGF
- Ihh
Indian hedgehog
- Kiss1
KiSS-1 metastasis suppressor
- Kiss1r
Kiss1 receptor
- LE
luminal epithelium
- Lef1
lymphoid enhancer binding factor 1
- Lgr
leucine-rich repeat–containing G protein–coupled receptor
- Lif
leukemia inhibitory factor
- LRP
low-density lipoprotein receptor–related protein
- Ltf
lactotransferrin
- P
postnatal day
- PDZ
primary decidual zone
- PGE2
prostaglandin E2
- PGR
progesterone receptor
- Porcn
porcupine homolog
- PRL
prolactin
- PRLR
PRL receptor
- PTGS2
prostaglandin-endoperoxide synthase 2
- PUGKO
progesterone-induced UGKO
- SDZ
secondary decidual zone
- SFRP
secreted FZD-related protein
- Spink1
serine peptidase inhibitor Kazal type 1
- STB
syncytiotrophoblast
- TE
trophectoderm
- UGKO
uterine gland knockout
- WNT
wingless-type mouse mammary tumor virus integration site family
References and Notes
- 1. Gray CA, Bartol FF, Tarleton BJ, Wiley AA, Johnson GA, Bazer FW, Spencer TE. Developmental biology of uterine glands. Biol Reprod. 2001;65(5):1311–1323. [DOI] [PubMed] [Google Scholar]
- 2. Cooke PS, Spencer TE, Bartol FF, Hayashi K. Uterine glands: development, function and experimental model systems. Mol Hum Reprod. 2013;19(9):547–558. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Spencer TE, Kelleher AM, Bartol FF. Development and function of uterine glands in domestic animals. Annu Rev Anim Biosci. 2019;7(1):125–147. [DOI] [PubMed] [Google Scholar]
- 4. Bazer FW. Uterine protein secretions: relationship to development of the conceptus. J Anim Sci. 1975;41(5):1376–1382. [DOI] [PubMed] [Google Scholar]
- 5. Roberts RM, Bazer FW. The functions of uterine secretions. J Reprod Fertil. 1988;82(2):875–892. [DOI] [PubMed] [Google Scholar]
- 6. Orvis GD, Behringer RR. Cellular mechanisms of Müllerian duct formation in the mouse. Dev Biol. 2007;306(2):493–504. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Massé J, Watrin T, Laurent A, Deschamps S, Guerrier D, Pellerin I. The developing female genital tract: from genetics to epigenetics. Int J Dev Biol. 2009;53(2–3):411–424. [DOI] [PubMed] [Google Scholar]
- 8. Kobayashi A, Behringer RR. Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet. 2003;4(12):969–980. [DOI] [PubMed] [Google Scholar]
- 9. Kurita T. Normal and abnormal epithelial differentiation in the female reproductive tract. Differentiation. 2011;82(3):117–126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Kurita T, Nakamura H. Embryology of the uterus. In: Aplin JD, Fazleabas AT, Giudice LC, eds. Endometrium. London, United Kingdom: Informa UK Ltd; 2008:1–18. [Google Scholar]
- 11. Bartol FF, Wiley AA, Floyd JG, Ott TL, Bazer FW, Gray CA, Spencer TE. Uterine differentiation as a foundation for subsequent fertility. J Reprod Fertil Suppl. 1999;54:287–302. [PubMed] [Google Scholar]
- 12. Bartol FF, Wiley AA, Spencer TE, Vallet JL, Christenson RK. Early uterine development in pigs. J Reprod Fertil Suppl. 1993;48:99–116. [PubMed] [Google Scholar]
- 13. Spencer TE, Dunlap KA, Filant J. Comparative developmental biology of the uterus: insights into mechanisms and developmental disruption. Mol Cell Endocrinol. 2012;354(1–2):34–53. [DOI] [PubMed] [Google Scholar]
- 14. Spencer TE, Hayashi K, Hu J, Carpenter KD. Comparative developmental biology of the mammalian uterus. Curr Top Dev Biol. 2005;68:85–122. [DOI] [PubMed] [Google Scholar]
- 15. O’Rahilly R. Prenatal human development. In: Wynn RM, Jollie WP, eds. Biology of the Uterus. New York, NY: Plenum Medical Book Company; 1989:35–55. [Google Scholar]
- 16. O’Rahilly R. The embryology and anatomy of the uterus. In: Norris HJ, Hertig AT, Abell MR, eds. The Uterus. Baltimore, MD: Williams & Wilkins; 1973:17–39. [Google Scholar]
- 17. Wooding FB. The synepitheliochorial placenta of ruminants: binucleate cell fusions and hormone production. Placenta. 1992;13(2):101–113. [DOI] [PubMed] [Google Scholar]
- 18. Vue Z, Gonzalez G, Stewart CA, Mehra S, Behringer RR. Volumetric imaging of the developing prepubertal mouse uterine epithelium using light sheet microscopy. Mol Reprod Dev. 2018;85(5):397–405. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Arora R, Fries A, Oelerich K, Marchuk K, Sabeur K, Giudice LC, Laird DJ. Insights from imaging the implanting embryo and the uterine environment in three dimensions. Development. 2016;143(24):4749–4754. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Yuan J, Deng W, Cha J, Sun X, Borg JP, Dey SK. Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation. Nat Commun. 2018;9(1):603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Goad J, Ko YA, Kumar M, Syed SM, Tanwar PS. Differential Wnt signaling activity limits epithelial gland development to the anti-mesometrial side of the mouse uterus. Dev Biol. 2017;423(2):138–151. [DOI] [PubMed] [Google Scholar]
- 22. Cunha GR, Robboy SJ, Kurita T, Isaacson D, Shen J, Cao M, Baskin LS. Development of the human female reproductive tract. Differentiation. 2018;103:46–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Soyal SM, Mukherjee A, Lee KY, Li J, Li H, DeMayo FJ, Lydon JP. Cre-mediated recombination in cell lineages that express the progesterone receptor. Genesis. 2005;41(2):58–66. [DOI] [PubMed] [Google Scholar]
- 24. Cui T, He B, Kong S, Zhou C, Zhang H, Ni Z, Bao H, Qiu J, Xin Q, Reinberg D, Lydon JP, Lu J, Wang H. PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice. Cell Death Differ. 2017;24(12):2013–2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Cunha GR. Stromal induction and specification of morphogenesis and cytodifferentiation of the epithelia of the Mullerian ducts and urogenital sinus during development of the uterus and vagina in mice. J Exp Zool. 1976;196(3):361–369. [DOI] [PubMed] [Google Scholar]
- 26. Cunha GR. Epithelial-stromal interactions in development of the urogenital tract. Int Rev Cytol. 1976;47:137–194. [DOI] [PubMed] [Google Scholar]
- 27. Sharpe PM, Ferguson MW. Mesenchymal influences on epithelial differentiation in developing systems. J Cell Sci Suppl. 1988;10:195–230. [DOI] [PubMed] [Google Scholar]
- 28. Ogasawara Y, Okamoto S, Kitamura Y, Matsumoto K. Proliferative pattern of uterine cells from birth to adulthood in intact, neonatally castrated, and/or adrenalectomized mice, assayed by incorporation of [125I]iododeoxyuridine. Endocrinology. 1983;113(2):582–587. [DOI] [PubMed] [Google Scholar]
- 29. Taylor KM, Gray CA, Joyce MM, Stewart MD, Bazer FW, Spencer TE. Neonatal ovine uterine development involves alterations in expression of receptors for estrogen, progesterone, and prolactin. Biol Reprod. 2000;63(4):1192–1204. [DOI] [PubMed] [Google Scholar]
- 30. Wiley AA, Bartol FF, Barron DH. Histogenesis of the ovine uterus. J Anim Sci. 1987;64(4):1262–1269. [DOI] [PubMed] [Google Scholar]
- 31. Bartol FF, Wiley AA, Goodlett DR. Ovine uterine morphogenesis: histochemical aspects of endometrial development in the fetus and neonate. J Anim Sci. 1988;66(5):1303–1313. [DOI] [PubMed] [Google Scholar]
- 32. Lopez EW, Vue Z, Broaddus RR, Behringer RR, Gladden AB. The ERM family member Merlin is required for endometrial gland morphogenesis. Dev Biol. 2018;442(2):301–314. [DOI] [PubMed] [Google Scholar]
- 33. Spencer TE, Carpenter KD, Hayashi K, Hu J. Uterine glands. In: Davies JA, ed. Branching Morphogenesis. Boston, MA: Springer; 2005:186–210. [Google Scholar]
- 34. Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149(6):1192–1205. [DOI] [PubMed] [Google Scholar]
- 35. Franco HL, Dai D, Lee KY, Rubel CA, Roop D, Boerboom D, Jeong JW, Lydon JP, Bagchi IC, Bagchi MK, DeMayo FJ. WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse. FASEB J. 2011;25(4):1176–1187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Dunlap KA, Filant J, Hayashi K, Rucker EB III, Song G, Deng JM, Behringer RR, DeMayo FJ, Lydon J, Jeong JW, Spencer TE. Postnatal deletion of Wnt7a inhibits uterine gland morphogenesis and compromises adult fertility in mice. Biol Reprod. 2011;85(2):386–396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Mericskay M, Kitajewski J, Sassoon D. Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus. Development. 2004;131(9):2061–2072. [DOI] [PubMed] [Google Scholar]
- 38. Shelton DN, Fornalik H, Neff T, Park SY, Bender D, DeGeest K, Liu X, Xie W, Meyerholz DK, Engelhardt JF, Goodheart MJ. The role of LEF1 in endometrial gland formation and carcinogenesis. PLoS One. 2012;7(7):e40312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Stewart CA, Wang Y, Bonilla-Claudio M, Martin JF, Gonzalez G, Taketo MM, Behringer RR. CTNNB1 in mesenchyme regulates epithelial cell differentiation during Müllerian duct and postnatal uterine development. Mol Endocrinol. 2013;27(9):1442–1454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Sugimura R, Li L. Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases. Birth Defects Res C Embryo Today. 2010;90(4):243–256. [DOI] [PubMed] [Google Scholar]
- 41. Jeong JW, Lee HS, Franco HL, Broaddus RR, Taketo MM, Tsai SY, Lydon JP, DeMayo FJ β-Catenin mediates glandular formation and dysregulation of β-catenin induces hyperplasia formation in the murine uterus. Oncogene. 2009;28(1):31–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Reardon SN, King ML, MacLean JA 2nd, Mann JL, DeMayo FJ, Lydon JP, Hayashi K. CDH1 is essential for endometrial differentiation, gland development, and adult function in the mouse uterus. Biol Reprod. 2012;86(5):141, 1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Miller C, Sassoon DA. Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract. Development. 1998;125(16):3201–3211. [DOI] [PubMed] [Google Scholar]
- 44. Miller C, Pavlova A, Sassoon DA. Differential expression patterns of Wnt genes in the murine female reproductive tract during development and the estrous cycle. Mech Dev. 1998;76(1–2):91–99. [DOI] [PubMed] [Google Scholar]
- 45. Hayashi K, Yoshioka S, Reardon SN, Rucker EB III, Spencer TE, DeMayo FJ, Lydon JP, MacLean JA II. WNTs in the neonatal mouse uterus: potential regulation of endometrial gland development. Biol Reprod. 2011;84(2):308–319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46. Miller C, Degenhardt K, Sassoon DA. Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis. Nat Genet. 1998;20(3):228–230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Carta L, Sassoon D. Wnt7a is a suppressor of cell death in the female reproductive tract and is required for postnatal and estrogen-mediated growth. Biol Reprod. 2004;71(2):444–454. [DOI] [PubMed] [Google Scholar]
- 48. Stark K, Vainio S, Vassileva G, McMahon AP. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 1994;372(6507):679–683. [DOI] [PubMed] [Google Scholar]
- 49. Hofmann K. A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem Sci. 2000;25(3):111–112. [DOI] [PubMed] [Google Scholar]
- 50. Najdi R, Proffitt K, Sprowl S, Kaur S, Yu J, Covey TM, Virshup DM, Waterman ML. A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities. Differentiation. 2012;84(2):203–213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Takada R, Satomi Y, Kurata T, Ueno N, Norioka S, Kondoh H, Takao T, Takada S. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell. 2006;11(6):791–801. [DOI] [PubMed] [Google Scholar]
- 52. Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC. Structural basis of Wnt recognition by Frizzled. Science. 2012;337(6090):59–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Farah O, Biechele S, Rossant J, Dufort D. Regulation of porcupine-dependent Wnt signaling is essential for uterine development and function. Reproduction. 2018;155(1):93–102. [DOI] [PubMed] [Google Scholar]
- 54. Cha J, Bartos A, Park C, Sun X, Li Y, Cha SW, Ajima R, Ho HY, Yamaguchi TP, Dey SK. Appropriate crypt formation in the uterus for embryo homing and implantation requires Wnt5a-ROR signaling. Cell Reports. 2014;8(2):382–392. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling. Proc Natl Acad Sci USA. 2011;108(28):11452–11457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56. Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D, Boutros M, Cruciat CM, Niehrs C. LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO Rep. 2011;12(10):1055–1061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57. Sone M, Oyama K, Mohri Y, Hayashi R, Clevers H, Nishimori K. LGR4 expressed in uterine epithelium is necessary for uterine gland development and contributes to decidualization in mice. FASEB J. 2013;27(12):4917–4928. [DOI] [PubMed] [Google Scholar]
- 58. Nusse R. Making head or tail of Dickkopf. Nature. 2001;411(6835):255–256. [DOI] [PubMed] [Google Scholar]
- 59. Hayashi K, Spencer TE. WNT pathways in the neonatal ovine uterus: potential specification of endometrial gland morphogenesis by SFRP2. Biol Reprod. 2006;74(4):721–733. [DOI] [PubMed] [Google Scholar]
- 60. Friedman JR, Kaestner KH. The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci. 2006;63(19–20):2317–2328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61. Kaestner KH. The FoxA factors in organogenesis and differentiation. Curr Opin Genet Dev. 2010;20(5):527–532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Bernardo GM, Lozada KL, Miedler JD, Harburg G, Hewitt SC, Mosley JD, Godwin AK, Korach KS, Visvader JE, Kaestner KH, Abdul-Karim FW, Montano MM, Keri RA. FOXA1 is an essential determinant of ERα expression and mammary ductal morphogenesis. Development. 2010;137(12):2045–2054. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. Lee CS, Sund NJ, Behr R, Herrera PL, Kaestner KH. Foxa2 is required for the differentiation of pancreatic α-cells. Dev Biol. 2005;278(2):484–495. [DOI] [PubMed] [Google Scholar]
- 64. Besnard V, Wert SE, Hull WM, Whitsett JA. Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues. Gene Expr Patterns. 2004;5(2):193–208. [DOI] [PubMed] [Google Scholar]
- 65. Filant J, Spencer TE. Cell-specific transcriptional profiling reveals candidate mechanisms regulating development and function of uterine epithelia in mice. Biol Reprod. 2013;89(4):86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Weinstein DC, Ruiz i Altaba A, Chen WS, Hoodless P, Prezioso VR, Jessell TM, Darnell JE Jr. The winged-helix transcription factor HNF-3β is required for notochord development in the mouse embryo. Cell. 1994;78(4):575–588. [DOI] [PubMed] [Google Scholar]
- 67. Jeong JW, Kwak I, Lee KY, Kim TH, Large MJ, Stewart CL, Kaestner KH, Lydon JP, DeMayo FJ. Foxa2 is essential for mouse endometrial gland development and fertility. Biol Reprod. 2010;83(3):396–403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68. Kelleher AM, Peng W, Pru JK, Pru CA, DeMayo FJ, Spencer TE. Forkhead box a2 (FOXA2) is essential for uterine function and fertility. Proc Natl Acad Sci USA. 2017;114(6):E1018–E1026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69. Filant J, Lydon JP, Spencer TE. Integrated chromatin immunoprecipitation sequencing and microarray analysis identifies FOXA2 target genes in the glands of the mouse uterus. FASEB J. 2014;28(1):230–243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70. Kelleher AM, Milano-Foster J, Behura SK, Spencer TE. Uterine glands coordinate on-time embryo implantation and impact endometrial decidualization for pregnancy success. Nat Commun. 2018;9(1):2435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71. Wang H, Tranguch S, Xie H, Hanley G, Das SK, Dey SK. Variation in commercial rodent diets induces disparate molecular and physiological changes in the mouse uterus. Proc Natl Acad Sci USA. 2005;102(28):9960–9965. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72. Wahlsten D, Bachmanov A, Finn DA, Crabbe JC. Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades. Proc Natl Acad Sci USA. 2006;103(44):16364–16369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73. Kelleher AM, Behura SK, Burns GW, Young SL, DeMayo FJ, Spencer TE. Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium. FASEB J. 2019;33:8543–8554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74. Wan H, Dingle S, Xu Y, Besnard V, Kaestner KH, Ang SL, Wert S, Stahlman MT, Whitsett JA. Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis. J Biol Chem. 2005;280(14):13809–13816. [DOI] [PubMed] [Google Scholar]
- 75. Tamplin OJ, Kinzel D, Cox BJ, Bell CE, Rossant J, Lickert H. Microarray analysis of Foxa2 mutant mouse embryos reveals novel gene expression and inductive roles for the gastrula organizer and its derivatives. BMC Genomics. 2008;9(1):511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76. Mucenski ML, Wert SE, Nation JM, Loudy DE, Huelsken J, Birchmeier W, Morrisey EE, Whitsett JA. β-Catenin is required for specification of proximal/distal cell fate during lung morphogenesis. J Biol Chem. 2003;278(41):40231–40238. [DOI] [PubMed] [Google Scholar]
- 77. Yu X, Wang Y, Jiang M, Bierie B, Roy-Burman P, Shen MM, Taketo MM, Wills M, Matusik RJ. Activation of β-catenin in mouse prostate causes HGPIN and continuous prostate growth after castration. Prostate. 2009;69(3):249–262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78. Wang X, Li X, Wang T, Wu SP, Jeong JW, Kim TH, Young SL, Lessey BA, Lanz RB, Lydon JP, DeMayo FJ. SOX17 regulates uterine epithelial–stromal cross-talk acting via a distal enhancer upstream of Ihh. Nat Commun. 2018;9(1):4421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79. Guimarães-Young A, Neff T, Dupuy AJ, Goodheart MJ. Conditional deletion of Sox17 reveals complex effects on uterine adenogenesis and function. Dev Biol. 2016;414(2):219–227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80. Robledo RF, Rajan L, Li X, Lufkin T. The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development. Genes Dev. 2002;16(9):1089–1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81. Beverdam A, Merlo GR, Paleari L, Mantero S, Genova F, Barbieri O, Janvier P, Levi G. Jaw transformation with gain of symmetry after Dlx5/Dlx6 inactivation: mirror of the past? Genesis. 2002;34(4):221–227. [DOI] [PubMed] [Google Scholar]
- 82. Bellessort B, Le Cardinal M, Bachelot A, Narboux-Nême N, Garagnani P, Pirazzini C, Barbieri O, Mastracci L, Jonchere V, Duvernois-Berthet E, Fontaine A, Alfama G, Levi G. Dlx5 and Dlx6 control uterine adenogenesis during post-natal maturation: possible consequences for endometriosis. Hum Mol Genet. 2016;25(1):97–108. [DOI] [PubMed] [Google Scholar]
- 83. Fishman RB, Branham WS, Streck RD, Sheehan DM. Ontogeny of estrogen receptor messenger ribonucleic acid expression in the postnatal rat uterus. Biol Reprod. 1996;55(6):1221–1230. [DOI] [PubMed] [Google Scholar]
- 84. Yamashita S, Newbold RR, McLachlan JA, Korach KS. Developmental pattern of estrogen receptor expression in female mouse genital tracts. Endocrinology. 1989;125(6):2888–2896. [DOI] [PubMed] [Google Scholar]
- 85. Korach KS, Horigome T, Tomooka Y, Yamashita S, Newbold RR, McLachlan JA. Immunodetection of estrogen receptor in epithelial and stromal tissues of neonatal mouse uterus. Proc Natl Acad Sci USA. 1988;85(10):3334–3337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86. Tarleton BJ, Wiley AA, Bartol FF. Endometrial development and adenogenesis in the neonatal pig: effects of estradiol valerate and the antiestrogen ICI 182,780. Biol Reprod. 1999;61(1):253–263. [DOI] [PubMed] [Google Scholar]
- 87. Tarleton BJ, Wiley AA, Spencer TE, Moss AG, Bartol FF. Ovary-independent estrogen receptor expression in neonatal porcine endometrium. Biol Reprod. 1998;58(4):1009–1019. [DOI] [PubMed] [Google Scholar]
- 88. Hewitt SC, Kissling GE, Fieselman KE, Jayes FL, Gerrish KE, Korach KS. Biological and biochemical consequences of global deletion of exon 3 from the ERα gene. FASEB J. 2010;24(12):4660–4667. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89. Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA. 1993;90(23):11162–11166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 90. Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O. Generation and reproductive phenotypes of mice lacking estrogen receptor β. Proc Natl Acad Sci USA. 1998;95(26):15677–15682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91. Stewart CA, Fisher SJ, Wang Y, Stewart MD, Hewitt SC, Rodriguez KF, Korach KS, Behringer RR. Uterine gland formation in mice is a continuous process, requiring the ovary after puberty, but not after parturition. Biol Reprod. 2011;85(5):954–964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92. Nanjappa MK, Medrano TI, March AG, Cooke PS. Neonatal uterine and vaginal cell proliferation and adenogenesis are independent of estrogen receptor 1 (ESR1) in the mouse. Biol Reprod. 2015;92(3):78. [DOI] [PubMed] [Google Scholar]
- 93. Safranski TJ, Lamberson WR, Keisler DH. Correlations among three measures of puberty in mice and relationships with estradiol concentration and ovulation. Biol Reprod. 1993;48(3):669–673. [DOI] [PubMed] [Google Scholar]
- 94. Mayer C, Acosta-Martinez M, Dubois SL, Wolfe A, Radovick S, Boehm U, Levine JE. Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons. Proc Natl Acad Sci USA. 2010;107(52):22693–22698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95. Carpenter KD, Gray CA, Bryan TM, Welsh TH Jr, Spencer TE. Estrogen and antiestrogen effects on neonatal ovine uterine development. Biol Reprod. 2003;69(2):708–717. [DOI] [PubMed] [Google Scholar]
- 96. Cooke PS, Buchanan DL, Lubahn DB, Cunha GR. Mechanism of estrogen action: lessons from the estrogen receptor-α knockout mouse. Biol Reprod. 1998;59(3):470–475. [DOI] [PubMed] [Google Scholar]
- 97. Cooke PS, Buchanan DL, Young P, Setiawan T, Brody J, Korach KS, Taylor J, Lubahn DB, Cunha GR. Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc Natl Acad Sci USA. 1997;94(12):6535–6540. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98. Hall JM, Couse JF, Korach KS. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem. 2001;276(40):36869–36872. [DOI] [PubMed] [Google Scholar]
- 99. Ignar-Trowbridge DM, Nelson KG, Bidwell MC, Curtis SW, Washburn TF, McLachlan JA, Korach KS. Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. Proc Natl Acad Sci USA. 1992;89(10):4658–4662. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100. Smith CL. Cross-talk between peptide growth factor and estrogen receptor signaling pathways. Biol Reprod. 1998;58(3):627–632. [DOI] [PubMed] [Google Scholar]
- 101. Gertler A, Djiane J. Mechanism of ruminant placental lactogen action: molecular and in vivo studies. Mol Genet Metab. 2002;75(3):189–201. [DOI] [PubMed] [Google Scholar]
- 102. Anthony RV, Limesand SW, Fanning MD, Liang R. Placental lactogen and growth hormone: regulation and action. In: Bazer FW, ed. The Endocrinology of Pregnancy. Totowa, NJ: Humana Press; 1998:461–490. [Google Scholar]
- 103. Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev. 2000;80(4):1523–1631. [DOI] [PubMed] [Google Scholar]
- 104. Carpenter KD, Gray CA, Noel S, Gertler A, Bazer FW, Spencer TE. Prolactin regulation of neonatal ovine uterine gland morphogenesis. Endocrinology. 2003;144(1):110–120. [DOI] [PubMed] [Google Scholar]
- 105. Jabbour HN, Critchley HO, Boddy SC. Expression of functional prolactin receptors in nonpregnant human endometrium: Janus kinase-2, signal transducer and activator of transcription-1 (STAT1), and STAT5 proteins are phosphorylated after stimulation with prolactin. J Clin Endocrinol Metab. 1998;83(7):2545–2553. [DOI] [PubMed] [Google Scholar]
- 106. Reese J, Binart N, Brown N, Ma WG, Paria BC, Das SK, Kelly PA, Dey SK. Implantation and decidualization defects in prolactin receptor (PRLR)-deficient mice are mediated by ovarian but not uterine PRLR. Endocrinology. 2000;141(5):1872–1881. [DOI] [PubMed] [Google Scholar]
- 107. Bigsby RM, Cunha GR. Effects of progestins and glucocorticoids on deoxyribonucleic acid synthesis in the uterus of the neonatal mouse. Endocrinology. 1985;117(6):2520–2526. [DOI] [PubMed] [Google Scholar]
- 108. Branham WS, Sheehan DM. Ovarian and adrenal contributions to postnatal growth and differentiation of the rat uterus. Biol Reprod. 1995;53(4):863–872. [DOI] [PubMed] [Google Scholar]
- 109. Bartol FF, Wiley AA, Coleman DA, Wolfe DF, Riddell MG. Ovine uterine morphogenesis: effects of age and progestin administration and withdrawal on neonatal endometrial development and DNA synthesis. J Anim Sci. 1988;66(11):3000–3009. [DOI] [PubMed] [Google Scholar]
- 110. Kennedy JP, Worthington CA, Cole ER. The post-natal development of the ovary and uterus of the Merino lamb. J Reprod Fertil. 1974;36(2):275–282. [DOI] [PubMed] [Google Scholar]
- 111. Hayashi K, Carpenter KD, Gray CA, Spencer TE. The activin-follistatin system in the neonatal ovine uterus. Biol Reprod. 2003;69(3):843–850. [DOI] [PubMed] [Google Scholar]
- 112. Carpenter KD, Hayashi K, Spencer TE. Ovarian regulation of endometrial gland morphogenesis and activin-follistatin system in the neonatal ovine uterus. Biol Reprod. 2003;69(3):851–860. [DOI] [PubMed] [Google Scholar]
- 113. Hayashi K, O’Connell AR, Juengel JL, McNatty KP, Davis GH, Bazer FW, Spencer TE. Postnatal uterine development in Inverdale ewe lambs. Reproduction. 2008;135(3):357–365. [DOI] [PubMed] [Google Scholar]
- 114. Montgomery GW, Galloway SM, Davis GH, McNatty KP. Genes controlling ovulation rate in sheep. Reproduction. 2001;121(6):843–852. [PubMed] [Google Scholar]
- 115. Bigsby RM, Caperell-Grant A, Berry N, Nephew K, Lubahn D. Estrogen induces a systemic growth factor through an estrogen receptor-alpha-dependent mechanism. Biol Reprod. 2004;70(1):178–183. [DOI] [PubMed] [Google Scholar]
- 116. León S, Fernandois D, Sull A, Sull J, Calder M, Hayashi K, Bhattacharya M, Power S, Vilos GA, Vilos AG, Tena-Sempere M, Babwah AV. Beyond the brain-Peripheral kisspeptin signaling is essential for promoting endometrial gland development and function (published correction appears in Sci Rep. 2016;6:30954). Sci Rep. 2016;6(1):29073. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117. Bartol FF, Bagnell CA. Lactocrine programming. In: Skinner MK, ed. Encyclopedia of Reproduction. Vol 2. 2nd ed. New York, NY: Academic Press; 2018:814–820. [Google Scholar]
- 118. Bartol FF, Wiley AA, George AF, Miller DJ, Bagnell CA. Physiology and endocrinology symposium: postnatal reproductive development and the lactocrine hypothesis. J Anim Sci. 2017;95(5):2200–2210. [DOI] [PubMed] [Google Scholar]
- 119. Bagnell CA, Ho TY, George AF, Wiley AA, Miller DJ, Bartol FF. Maternal lactocrine programming of porcine reproductive tract development. Mol Reprod Dev. 2017;84(9):957–968. [DOI] [PubMed] [Google Scholar]
- 120. Bartol FF, Wiley AA, Bagnell CA. Epigenetic programming of porcine endometrial function and the lactocrine hypothesis. Reprod Domest Anim. 2008;43(Suppl 2):273–279. [DOI] [PubMed] [Google Scholar]
- 121. Yan W, Wiley AA, Bathgate RA, Frankshun AL, Lasano S, Crean BD, Steinetz BG, Bagnell CA, Bartol FF. Expression of LGR7 and LGR8 by neonatal porcine uterine tissues and transmission of milk-borne relaxin into the neonatal circulation by suckling. Endocrinology. 2006;147(9):4303–4310. [DOI] [PubMed] [Google Scholar]
- 122. Masters RA, Crean BD, Yan W, Moss AG, Ryan PL, Wiley AA, Bagnell CA, Bartol FF. Neonatal porcine endometrial development and epithelial proliferation affected by age and exposure to estrogen and relaxin. Domest Anim Endocrinol. 2007;33(3):335–346. [DOI] [PubMed] [Google Scholar]
- 123. Klobasa F, Werhahn E, Butler JE. Composition of sow milk during lactation. J Anim Sci. 1987;64(5):1458–1466. [DOI] [PubMed] [Google Scholar]
- 124. Lecce JG, Morgan DO. Effect of dietary regimen on cessation of intestinal absorption of large molecules (closure) in the neonatal pig and lamb. J Nutr. 1962;78(3):263–268. [DOI] [PubMed] [Google Scholar]
- 125. George AF, Rahman KM, Miller DJ, Wiley AA, Camp ME, Bartol FF, Bagnell CA. Effects of colostrum, feeding method and oral IGF1 on porcine uterine development. Reproduction. 2018;155(3):259–271. [DOI] [PubMed] [Google Scholar]
- 126. Miller DJ, Wiley AA, Chen JC, Bagnell CA, Bartol FF. Nursing for 48 hours from birth supports porcine uterine gland development and endometrial cell compartment-specific gene expression. Biol Reprod. 2013;88(1):4. [DOI] [PubMed] [Google Scholar]
- 127. Bagnell CA, Bartol FF. Relaxin and the “Milky Way”: the lactocrine hypothesis and maternal programming of development. Mol Cell Endocrinol. 2019;487:18–23. [DOI] [PubMed] [Google Scholar]
- 128. Crain DA, Janssen SJ, Edwards TM, Heindel J, Ho SM, Hunt P, Iguchi T, Juul A, McLachlan JA, Schwartz J, Skakkebaek N, Soto AM, Swan S, Walker C, Woodruff TK, Woodruff TJ, Giudice LC, Guillette LJ Jr. Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing. Fertil Steril. 2008;90(4):911–940. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 129. Guillette LJ, Crain DA. Environmental Endocrine Disruptors: An Evolutionary Perspective. New York, NY: Taylor & Francis; 2000. [Google Scholar]
- 130. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284(15):878–881. [DOI] [PubMed] [Google Scholar]
- 131. Sananès N, Baulieu EE, Le Goascogne C. Treatment of neonatal rats with progesterone alters the capacity of the uterus to form deciduomata. J Reprod Fertil. 1980;58(1):271–273. [DOI] [PubMed] [Google Scholar]
- 132. Halling A, Forsberg JG. Acute and permanent growth effects in the mouse uterus after neonatal treatment with estrogens. Reprod Toxicol. 1993;7(2):137–153. [DOI] [PubMed] [Google Scholar]
- 133. Branham WS, Sheehan DM, Zehr DR, Ridlon E, Nelson CJ. The postnatal ontogeny of rat uterine glands and age-related effects of 17β-estradiol. Endocrinology. 1985;117(5):2229–2237. [DOI] [PubMed] [Google Scholar]
- 134. Medlock KL, Branham WS, Sheehan DM. Effects of toremifene on neonatal rat uterine growth and differentiation. Biol Reprod. 1997;56(5):1239–1244. [DOI] [PubMed] [Google Scholar]
- 135. Branham WS, Sheehan DM, Zehr DR, Medlock KL, Nelson CJ, Ridlon E. Inhibition of rat uterine gland genesis by tamoxifen. Endocrinology. 1985;117(5):2238–2248. [DOI] [PubMed] [Google Scholar]
- 136. Bartol FF, Johnson LL, Floyd JG, Wiley AA, Spencer TE, Buxton DF, Coleman DA. Neonatal exposure to progesterone and estradiol alters uterine morphology and luminal protein content in adult beef heifers. Theriogenology. 1995;43(5):835–844. [DOI] [PubMed] [Google Scholar]
- 137. Spencer TE, Wiley AA, Bartol FF. Neonatal age and period of estrogen exposure affect porcine uterine growth, morphogenesis, and protein synthesis. Biol Reprod. 1993;48(4):741–751. [DOI] [PubMed] [Google Scholar]
- 138. Tarleton BJ, Wiley AA, Bartol FF. Neonatal estradiol exposure alters uterine morphology and endometrial transcriptional activity in prepubertal gilts. Domest Anim Endocrinol. 2001;21(2):111–125. [DOI] [PubMed] [Google Scholar]
- 139. Tarleton BJ, Braden TD, Wiley AA, Bartol FF. Estrogen-induced disruption of neonatal porcine uterine development alters adult uterine function. Biol Reprod. 2003;68(4):1387–1393. [DOI] [PubMed] [Google Scholar]
- 140. Hayashi K, Carpenter KD, Spencer TE. Neonatal estrogen exposure disrupts uterine development in the postnatal sheep. Endocrinology. 2004;145(7):3247–3257. [DOI] [PubMed] [Google Scholar]
- 141. Allison Gray C, Bartol FF, Taylor KM, Wiley AA, Ramsey WS, Ott TL, Bazer FW, Spencer TE. Ovine uterine gland knock-out model: effects of gland ablation on the estrous cycle. Biol Reprod. 2000;62(2):448–456. [DOI] [PubMed] [Google Scholar]
- 142. Gray CA, Bazer FW, Spencer TE. Effects of neonatal progestin exposure on female reproductive tract structure and function in the adult ewe. Biol Reprod. 2001;64(3):797–804. [DOI] [PubMed] [Google Scholar]
- 143. Gray CA, Burghardt RC, Johnson GA, Bazer FW, Spencer TE. Evidence that absence of endometrial gland secretions in uterine gland knockout ewes compromises conceptus survival and elongation. Reproduction. 2002;124(2):289–300. [PubMed] [Google Scholar]
- 144. Filant J, Zhou H, Spencer TE. Progesterone inhibits uterine gland development in the neonatal mouse uterus. Biol Reprod. 2012;86(5):146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145. Cooke PS, Ekman GC, Kaur J, Davila J, Bagchi IC, Clark SG, Dziuk PJ, Hayashi K, Bartol FF. Brief exposure to progesterone during a critical neonatal window prevents uterine gland formation in mice. Biol Reprod. 2012;86(3):63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 146. Cunha GR, Bigsby RM, Cooke PS, Sugimura Y. Stromal-epithelial interactions in adult organs. Cell Differ. 1985;17(3):137–148. [DOI] [PubMed] [Google Scholar]
- 147. Kurita T, Cooke PS, Cunha GR. Epithelial-stromal tissue interaction in paramesonephric (Müllerian) epithelial differentiation. Dev Biol. 2001;240(1):194–211. [DOI] [PubMed] [Google Scholar]
- 148. Lee K, Jeong J, Tsai MJ, Tsai S, Lydon JP, DeMayo FJ. Molecular mechanisms involved in progesterone receptor regulation of uterine function. J Steroid Biochem Mol Biol. 2006;102(1–5):41–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 149. Lee K, Jeong J, Kwak I, Yu CT, Lanske B, Soegiarto DW, Toftgard R, Tsai MJ, Tsai S, Lydon JP, DeMayo FJ. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat Genet. 2006;38(10):1204–1209. [DOI] [PubMed] [Google Scholar]
- 150. Franco HL, Lee KY, Rubel CA, Creighton CJ, White LD, Broaddus RR, Lewis MT, Lydon JP, Jeong JW, DeMayo FJ. Constitutive activation of smoothened leads to female infertility and altered uterine differentiation in the mouse. Biol Reprod. 2010;82(5):991–999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151. Franco HL, Lee KY, Broaddus RR, White LD, Lanske B, Lydon JP, Jeong JW, DeMayo FJ. Ablation of Indian hedgehog in the murine uterus results in decreased cell cycle progression, aberrant epidermal growth factor signaling, and increased estrogen signaling. Biol Reprod. 2010;82(4):783–790. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152. Franco HL, Rubel CA, Large MJ, Wetendorf M, Fernandez-Valdivia R, Jeong JW, Spencer TE, Behringer RR, Lydon JP, Demayo FJ. Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function. FASEB J. 2012;26(3):1218–1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 153. Kelleher AM, Burns GW, Behura S, Wu G, Spencer TE. Uterine glands impact uterine receptivity, luminal fluid homeostasis and blastocyst implantation. Sci Rep. 2016;6(1):38078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 154. Burton GJ, Jauniaux E, Charnock-Jones DS. Human early placental development: potential roles of the endometrial glands. Placenta. 2007;28(Suppl A):S64–S69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 155. Gray CA, Taylor KM, Bazer FW, Spencer TE. Mechanisms regulating norgestomet inhibition of endometrial gland morphogenesis in the neonatal ovine uterus. Mol Reprod Dev. 2000;57(1):67–78. [DOI] [PubMed] [Google Scholar]
- 156. Gray CA, Taylor KM, Ramsey WS, Hill JR, Bazer FW, Bartol FF, Spencer TE. Endometrial glands are required for preimplantation conceptus elongation and survival. Biol Reprod. 2001;64(6):1608–1613. [DOI] [PubMed] [Google Scholar]
- 157. Spencer TE, Sandra O, Wolf E. Genes involved in conceptus–endometrial interactions in ruminants: insights from reductionism and thoughts on holistic approaches. Reproduction. 2008;135(2):165–179. [DOI] [PubMed] [Google Scholar]
- 158. Bazer FW, Wu G, Spencer TE, Johnson GA, Burghardt RC, Bayless K. Novel pathways for implantation and establishment and maintenance of pregnancy in mammals. Mol Hum Reprod. 2010;16(3):135–152. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 159. Dorniak P, Bazer FW, Spencer TE. Physiology and endocrinology symposium: biological role of interferon tau in endometrial function and conceptus elongation. J Anim Sci. 2013;91(4):1627–1638. [DOI] [PubMed] [Google Scholar]
- 160. Romero JJ, Liebig BE, Broeckling CD, Prenni JE, Hansen TR. Pregnancy-induced changes in metabolome and proteome in ovine uterine flushings. Biol Reprod. 2017;97(2):273–287. [DOI] [PubMed] [Google Scholar]
- 161. Brooks K, Burns GW, Moraes JG, Spencer TE. Analysis of the uterine epithelial and conceptus transcriptome and luminal fluid proteome during the peri-implantation period of pregnancy in sheep. Biol Reprod. 2016;95(4):88. [DOI] [PubMed] [Google Scholar]
- 162. Wang X, Frank JW, Little DR, Dunlap KA, Satterfield MC, Burghardt RC, Hansen TR, Wu G, Bazer FW. Functional role of arginine during the peri-implantation period of pregnancy. I. Consequences of loss of function of arginine transporter SLC7A1 mRNA in ovine conceptus trophectoderm. FASEB J. 2014;28(7):2852–2863. [DOI] [PubMed] [Google Scholar]
- 163. Filant J, Spencer TE. Endometrial glands are essential for blastocyst implantation and decidualization in the mouse uterus. Biol Reprod. 2013;88(4):93. [DOI] [PubMed] [Google Scholar]
- 164. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, Abbondanzo SJ. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359(6390):76–79. [DOI] [PubMed] [Google Scholar]
- 165. Niklaus AL, Pollard JW. Mining the mouse transcriptome of receptive endometrium reveals distinct molecular signatures for the luminal and glandular epithelium. Endocrinology. 2006;147(7):3375–3390. [DOI] [PubMed] [Google Scholar]
- 166. Harris SE, Gopichandran N, Picton HM, Leese HJ, Orsi NM. Nutrient concentrations in murine follicular fluid and the female reproductive tract. Theriogenology. 2005;64(4):992–1006. [DOI] [PubMed] [Google Scholar]
- 167. Chen W, Han BC, Wang RC, Xiong GF, Peng JP. Role of secretory protease inhibitor SPINK3 in mouse uterus during early pregnancy. Cell Tissue Res. 2010;341(3):441–451. [DOI] [PubMed] [Google Scholar]
- 168. Large MJ, DeMayo FJ. The regulation of embryo implantation and endometrial decidualization by progesterone receptor signaling. Mol Cell Endocrinol. 2012;358(2):155–165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 169. Dey SK, Lim H, Das SK, Reese J, Paria BC, Daikoku T, Wang H. Molecular cues to implantation. Endocr Rev. 2004;25(3):341–373. [DOI] [PubMed] [Google Scholar]
- 170. Psychoyos A. Hormonal control of ovoimplantation. Vitam Horm. 1973;31:201–256. [DOI] [PubMed] [Google Scholar]
- 171. Ma WG, Song H, Das SK, Paria BC, Dey SK. Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc Natl Acad Sci USA. 2003;100(5):2963–2968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 172. Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006;7(3):185–199. [DOI] [PubMed] [Google Scholar]
- 173. Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754–1767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 174. Enders AC, Schlafke S. Cytological aspects of trophoblast-uterine interaction in early implantation. Am J Anat. 1969;125(1):1–29. [DOI] [PubMed] [Google Scholar]
- 175. Gellersen B, Brosens IA, Brosens JJ. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007;25(6):445–453. [DOI] [PubMed] [Google Scholar]
- 176. Ramathal CY, Bagchi IC, Taylor RN, Bagchi MK. Endometrial decidualization: of mice and men. Semin Reprod Med. 2010;28(1):17–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 177. Das SK. Cell cycle regulatory control for uterine stromal cell decidualization in implantation. Reproduction. 2009;137(6):889–899. [DOI] [PubMed] [Google Scholar]
- 178. Qi QR, Zhao XY, Zuo RJ, Wang TS, Gu XW, Liu JL, Yang ZM. Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization. Cell Cycle. 2015;14(12):1842–1858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179. Das SK. Regional development of uterine decidualization: molecular signaling by Hoxa-10. Mol Reprod Dev. 2010;77(5):387–396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 180. Das A, Mantena SR, Kannan A, Evans DB, Bagchi MK, Bagchi IC. De novo synthesis of estrogen in pregnant uterus is critical for stromal decidualization and angiogenesis (published correction appears in Proc Natl Acad Sci USA. 2009;106(37):16003). Proc Natl Acad Sci USA. 2009;106(30):12542–12547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 181. Li Q, Kannan A, Wang W, Demayo FJ, Taylor RN, Bagchi MK, Bagchi IC. Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. J Biol Chem. 2007;282(43):31725–31732. [DOI] [PubMed] [Google Scholar]
- 182. Tan J, Raja S, Davis MK, Tawfik O, Dey SK, Das SK. Evidence for coordinated interaction of cyclin D3 with p21 and cdk6 in directing the development of uterine stromal cell decidualization and polyploidy during implantation. Mech Dev. 2002;111(1–2):99–113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 183. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014;35(6):851–905. [DOI] [PubMed] [Google Scholar]
- 184. González IM, Martin PM, Burdsal C, Sloan JL, Mager S, Harris T, Sutherland AE. Leucine and arginine regulate trophoblast motility through mTOR-dependent and independent pathways in the preimplantation mouse embryo. Dev Biol. 2012;361(2):286–300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 185. Martin PM, Sutherland AE, Van Winkle LJ. Amino acid transport regulates blastocyst implantation. Biol Reprod. 2003;69(4):1101–1108. [DOI] [PubMed] [Google Scholar]
- 186. Martin PM, Sutherland AE. Exogenous amino acids regulate trophectoderm differentiation in the mouse blastocyst through an mTOR-dependent pathway. Dev Biol. 2001;240(1):182–193. [DOI] [PubMed] [Google Scholar]
- 187. Ramin N, Thieme R, Fischer S, Schindler M, Schmidt T, Fischer B, Navarrete Santos A. Maternal diabetes impairs gastrulation and insulin and IGF-I receptor expression in rabbit blastocysts. Endocrinology. 2010;151(9):4158–4167. [DOI] [PubMed] [Google Scholar]
- 188. Moley KH, Vaughn WK, DeCherney AH, Diamond MP. Effect of diabetes mellitus on mouse pre-implantation embryo development. J Reprod Fertil. 1991;93(2):325–332. [DOI] [PubMed] [Google Scholar]
- 189. Vercheval M, De Hertogh R, Pampfer S, Vanderheyden I, Michiels B, De Bernardi P, De Meyer R. Experimental diabetes impairs rat embryo development during the preimplantation period. Diabetologia. 1990;33(4):187–191. [DOI] [PubMed] [Google Scholar]
- 190. Pantaleon M, Tan HY, Kafer GR, Kaye PL. Toxic effects of hyperglycemia are mediated by the hexosamine signaling pathway and O-linked glycosylation in early mouse embryos. Biol Reprod. 2010;82(4):751–758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 191. Wyman A, Pinto AB, Sheridan R, Moley KH. One-cell zygote transfer from diabetic to nondiabetic mouse results in congenital malformations and growth retardation in offspring. Endocrinology. 2008;149(2):466–469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 192. Frolova AI, Moley KH. Glucose transporters in the uterus: an analysis of tissue distribution and proposed physiological roles. Reproduction. 2011;142(2):211–220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 193. Renfree MB, Shaw G. Embryo-endometrial interactions during early development after embryonic diapause in the marsupial tammar wallaby. Int J Dev Biol. 2014;58(2-4):175–181. [DOI] [PubMed] [Google Scholar]
- 194. Fenelon JC, Lefèvre PL, Banerjee A, Murphy BD. Regulation of diapause in carnivores. Reprod Domest Anim. 2017;52(Suppl 2):12–17. [DOI] [PubMed] [Google Scholar]
- 195. Filant J, Spencer TE. Uterine glands: biological roles in conceptus implantation, uterine receptivity and decidualization. Int J Dev Biol. 2014;58(2–4):107–116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 196. Spencer TE. Biological roles of uterine glands in pregnancy. Semin Reprod Med. 2014;32(5):346–357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 197. Salamonsen LA, Evans J, Nguyen HP, Edgell TA. The microenvironment of human implantation: determinant of reproductive success. Am J Reprod Immunol. 2016;75(3):218–225. [DOI] [PubMed] [Google Scholar]
- 198. Carson DD, Bagchi I, Dey SK, Enders AC, Fazleabas AT, Lessey BA, Yoshinaga K. Embryo implantation. Dev Biol. 2000;223(2):217–237. [DOI] [PubMed] [Google Scholar]
- 199. Rosario GX, Stewart CL. The multifaceted actions of leukaemia inhibitory factor in mediating uterine receptivity and embryo implantation. Am J Reprod Immunol. 2016;75(3):246–255. [DOI] [PubMed] [Google Scholar]
- 200. Chen JR, Cheng JG, Shatzer T, Sewell L, Hernandez L, Stewart CL. Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology. 2000;141(12):4365–4372. [DOI] [PubMed] [Google Scholar]
- 201. Bhatt H, Brunet LJ, Stewart CL. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl Acad Sci USA. 1991;88(24):11408–11412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 202. Daikoku T, Cha J, Sun X, Tranguch S, Xie H, Fujita T, Hirota Y, Lydon J, DeMayo F, Maxson R, Dey SK. Conditional deletion of MSX homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. Dev Cell. 2011;21(6):1014–1025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 203. Daikoku T, Ogawa Y, Terakawa J, Ogawa A, DeFalco T, Dey SK. Lactoferrin-iCre: a new mouse line to study uterine epithelial gene function. Endocrinology. 2014;155(7):2718–2724. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 204. Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet. 2011;43(1):27–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 205. Li Z, Tuteja G, Schug J, Kaestner KH. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell. 2012;148(1–2):72–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 206. Das SK, Wang XN, Paria BC, Damm D, Abraham JA, Klagsbrun M, Andrews GK, Dey SK. Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. Development. 1994;120(5):1071–1083. [DOI] [PubMed] [Google Scholar]
- 207. Yuan J, Cha J, Deng W, Bartos A, Sun X, Ho HH, Borg JP, Yamaguchi TP, Yang Y, Dey SK. Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci USA. 2016;113(50):E8079–E8088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 208. Deb K, Reese J, Paria BC. Methodologies to study implantation in mice. Methods Mol Med. 2006;121:9–34. [DOI] [PubMed] [Google Scholar]
- 209. Shuya LL, Menkhorst EM, Yap J, Li P, Lane N, Dimitriadis E. Leukemia inhibitory factor enhances endometrial stromal cell decidualization in humans and mice. PLoS One. 2011;6(9):e25288. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 210. Behura SK, Kelleher AM, Spencer TE. Evidence for functional interactions between the placenta and brain in pregnant mice. FASEB J. 2019;33(3):4261–4272. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 211. Burton GJ, Watson AL, Hempstock J, Skepper JN, Jauniaux E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J Clin Endocrinol Metab. 2002;87(6):2954–2959. [DOI] [PubMed] [Google Scholar]
- 212. Rogers PA, Polson D, Murphy CR, Hosie M, Susil B, Leoni M. Correlation of endometrial histology, morphometry, and ultrasound appearance after different stimulation protocols for in vitro fertilization. Fertil Steril. 1991;55(3):583–587. [DOI] [PubMed] [Google Scholar]
- 213. Evans GE, Martínez-Conejero JA, Phillipson GT, Simón C, McNoe LA, Sykes PH, Horcajadas JA, Lam EY, Print CG, Sin IL, Evans JJ. Gene and protein expression signature of endometrial glandular and stromal compartments during the window of implantation. Fertil Steril. 2012;97(6):1365–1373.e1–2. [DOI] [PubMed] [Google Scholar]
- 214. Hannan NJ, Stephens AN, Rainczuk A, Hincks C, Rombauts LJ, Salamonsen LA. 2D-DiGE analysis of the human endometrial secretome reveals differences between receptive and nonreceptive states in fertile and infertile women. J Proteome Res. 2010;9(12):6256–6264. [DOI] [PubMed] [Google Scholar]
- 215. Scotchie JG, Fritz MA, Mocanu M, Lessey BA, Young SL. Proteomic analysis of the luteal endometrial secretome. Reprod Sci. 2009;16(9):883–893. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 216. Casado-Vela J, Rodriguez-Suarez E, Iloro I, Ametzazurra A, Alkorta N, García-Velasco JA, Matorras R, Prieto B, González S, Nagore D, Simón L, Elortza F. Comprehensive proteomic analysis of human endometrial fluid aspirate. J Proteome Res. 2009;8(10):4622–4632. [DOI] [PubMed] [Google Scholar]
- 217. Vilella F, Ramirez LB, Simón C. Lipidomics as an emerging tool to predict endometrial receptivity. Fertil Steril. 2013;99(4):1100–1106. [DOI] [PubMed] [Google Scholar]
- 218. Boomsma CM, Kavelaars A, Eijkemans MJ, Amarouchi K, Teklenburg G, Gutknecht D, Fauser BJ, Heijnen CJ, Macklon NS. Cytokine profiling in endometrial secretions: a non-invasive window on endometrial receptivity. Reprod Biomed Online. 2009;18(1):85–94. [DOI] [PubMed] [Google Scholar]
- 219. Hannan NJ, Stoikos CJ, Stephens AN, Salamonsen LA. Depletion of high-abundance serum proteins from human uterine lavages enhances detection of lower-abundance proteins. J Proteome Res. 2009;8(2):1099–1103. [DOI] [PubMed] [Google Scholar]
- 220. Ng YH, Rome S, Jalabert A, Forterre A, Singh H, Hincks CL, Salamonsen LA. Endometrial exosomes/microvesicles in the uterine microenvironment: a new paradigm for embryo-endometrial cross talk at implantation. PLoS One. 2013;8(3):e58502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 221. Kane MT, Morgan PM, Coonan C. Peptide growth factors and preimplantation development. Hum Reprod Update. 1997;3(2):137–157. [DOI] [PubMed] [Google Scholar]
- 222. Hempstock J, Cindrova-Davies T, Jauniaux E, Burton GJ. Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy: a morphological and immunohistochemical study. Reprod Biol Endocrinol. 2004;2(1):58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 223. Salamonsen LA, Hannan NJ, Dimitriadis E. Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation. Semin Reprod Med. 2007;25(6):437–444. [DOI] [PubMed] [Google Scholar]
- 224. Salamonsen LA, Edgell T, Rombauts LJ, Stephens AN, Robertson DM, Rainczuk A, Nie G, Hannan NJ. Proteomics of the human endometrium and uterine fluid: a pathway to biomarker discovery. Fertil Steril. 2013;99(4):1086–1092. [DOI] [PubMed] [Google Scholar]
- 225. Cheong Y, Boomsma C, Heijnen C, Macklon N. Uterine secretomics: a window on the maternal-embryo interface. Fertil Steril. 2013;99(4):1093–1099. [DOI] [PubMed] [Google Scholar]
- 226. Burton GJ, Jauniaux E, Charnock-Jones DS. The influence of the intrauterine environment on human placental development. Int J Dev Biol. 2010;54(2–3):303–312. [DOI] [PubMed] [Google Scholar]
- 227. Burton GJ, Scioscia M, Rademacher TW. Endometrial secretions: creating a stimulatory microenvironment within the human early placenta and implications for the aetiopathogenesis of preeclampsia. J Reprod Immunol. 2011;89(2):118–125. [DOI] [PubMed] [Google Scholar]
- 228. Wooding FB, Burton GJ. Comparative Placentation: Structures, Functions and Evolution. Berlin, Germany: Springer; 2008.
- 229. Red-Horse K, Zhou Y, Genbacev O, Prakobphol A, Foulk R, McMaster M, Fisher SJ. Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest. 2004;114(6):744–754. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 230. Hamilton WJ, Boyd JD. Development of the human placenta in the first three months of gestation. J Anat. 1960;94:297–328. [PMC free article] [PubMed] [Google Scholar]
- 231. Hamilton WJ, Gladstone RJ. A presomite human embryo (Shaw): the implantation. J Anat. 1942;76(Pt 2):187–203. [PMC free article] [PubMed] [Google Scholar]
- 232. Moser G, Weiss G, Gauster M, Sundl M, Huppertz B. Evidence from the very beginning: endoglandular trophoblasts penetrate and replace uterine glands in situ and in vitro. Hum Reprod. 2015;30(12):2747–2757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 233. Burton GJ, Jaunaiux E. Maternal vascularisation of the human placenta: does the embryo develop in a hypoxic environment? Gynécol Obstét Fertil. 2001;29(7–8):503–508. [DOI] [PubMed] [Google Scholar]
- 234. Falkiner NM. A description of a human ovum fifteen days old with special reference to the vascular arrangements and to the morphology of the trophoblast. J Obstet Gynaecol Br Emp. 1932;39(3):471–506. [Google Scholar]
- 235. Arias-Stella J. Atypical endometrial changes associated with the presence of chorionic tissue. AMA Arch Pathol. 1954;58(2):112–128. [PubMed] [Google Scholar]
- 236. Arias-Stella J. The Arias-Stella reaction: facts and fancies four decades after. Adv Anat Pathol. 2002;9(1):12–23. [DOI] [PubMed] [Google Scholar]
- 237. Moser G, Windsperger K, Pollheimer J, de Sousa Lopes SC, Huppertz B. Human trophoblast invasion: new and unexpected routes and functions. Histochem Cell Biol. 2018;150(4):361–370. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 238. Moser G, Gauster M, Orendi K, Glasner A, Theuerkauf R, Huppertz B. Endoglandular trophoblast, an alternative route of trophoblast invasion? Analysis with novel confrontation co-culture models. Hum Reprod. 2010;25(5):1127–1136. [DOI] [PubMed] [Google Scholar]
- 239. Moser G, Huppertz B. Implantation and extravillous trophoblast invasion: from rare archival specimens to modern biobanking. Placenta. 2017;56:19–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 240. Vento-Tormo R, Efremova M, Botting RA, Turco MY, Vento-Tormo M, Meyer KB, Park JE, Stephenson E, Polański K, Goncalves A, Gardner L, Holmqvist S, Henriksson J, Zou A, Sharkey AM, Millar B, Innes B, Wood L, Wilbrey-Clark A, Payne RP, Ivarsson MA, Lisgo S, Filby A, Rowitch DH, Bulmer JN, Wright GJ, Stubbington MJT, Haniffa M, Moffett A, Teichmann SA. Single-cell reconstruction of the early maternal–fetal interface in humans. Nature. 2018;563(7731):347–353. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 241. Hustin J, Schaaps JP. Echographic [corrected] and anatomic studies of the maternotrophoblastic border during the first trimester of pregnancy (published correction appears in Am J Obstet Gynecol. 1987;157(5):1291). Am J Obstet Gynecol. 1987;157(1):162–168. [DOI] [PubMed] [Google Scholar]
- 242. Jauniaux E, Gulbis B, Burton GJ. The human first trimester gestational sac limits rather than facilitates oxygen transfer to the foetus—a review. Placenta. 2003;24(Suppl A):S86–S93. [DOI] [PubMed] [Google Scholar]
- 243. Foidart JM, Hustin J, Dubois M, Schaaps JP. The human placenta becomes haemochorial at the 13th week of pregnancy. Int J Dev Biol. 1992;36(3):451–453. [PubMed] [Google Scholar]
- 244. Leese HJ. What does an embryo need? Hum Fertil (Camb). 2003;6(4):180–185. [DOI] [PubMed] [Google Scholar]
- 245. Watkins AJ, Papenbrock T, Fleming TP. The preimplantation embryo: handle with care. Semin Reprod Med. 2008;26(2):175–185. [DOI] [PubMed] [Google Scholar]
- 246. Bazer FW, Spencer TE, Johnson GA, Burghardt RC. Uterine receptivity to implantation of blastocysts in mammals. Front Biosci (Schol Ed). 2011;3(2):745–767. [DOI] [PubMed] [Google Scholar]
- 247. Seppälä M, Julkunen M, Riittinen L, Koistinen R. Endometrial proteins: a reappraisal. Hum Reprod. 1992;7(Suppl 1):31–38. [DOI] [PubMed] [Google Scholar]
- 248. Roberts RM, Fisher SJ. Trophoblast stem cells. Biol Reprod. 2011;84(3):412–421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 249. Maruo T, Matsuo H, Murata K, Mochizuki M. Gestational age-dependent dual action of epidermal growth factor on human placenta early in gestation. J Clin Endocrinol Metab. 1992;75(5):1362–1367. [DOI] [PubMed] [Google Scholar]
- 250. Spencer TE, Johnson GA, Burghardt RC, Bazer FW. Progesterone and placental hormone actions on the uterus: insights from domestic animals. Biol Reprod. 2004;71(1):2–10. [DOI] [PubMed] [Google Scholar]
- 251. Kleis-SanFrancisco S, Hewetson A, Chilton BS. Prolactin augments progesterone-dependent uteroglobin gene expression by modulating promoter-binding proteins. Mol Endocrinol. 1993;7(2):214–223. [DOI] [PubMed] [Google Scholar]
- 252. Spencer TE, Johnson GA, Bazer FW, Burghardt RC. Fetal-maternal interactions during the establishment of pregnancy in ruminants. Soc Reprod Fertil Suppl. 2007;64:379–396. [DOI] [PubMed] [Google Scholar]
- 253. Noel S, Herman A, Johnson GA, Gray CA, Stewart MD, Bazer FW, Gertler A, Spencer TE. Ovine placental lactogen specifically binds to endometrial glands of the ovine uterus. Biol Reprod. 2003;68(3):772–780. [DOI] [PubMed] [Google Scholar]
- 254. Stewart MD, Johnson GA, Gray CA, Burghardt RC, Schuler LA, Joyce MM, Bazer FW, Spencer TE. Prolactin receptor and uterine milk protein expression in the ovine endometrium during the estrous cycle and pregnancy. Biol Reprod. 2000;62(6):1779–1789. [DOI] [PubMed] [Google Scholar]
- 255. Wang H, Critchley HO, Kelly RW, Shen D, Baird DT. Progesterone receptor subtype B is differentially regulated in human endometrial stroma. Mol Hum Reprod. 1998;4(4):407–412. [DOI] [PubMed] [Google Scholar]
- 256. Zhou XL, Lei ZM, Rao CV. Treatment of human endometrial gland epithelial cells with chorionic gonadotropin/luteinizing hormone increases the expression of the cyclooxygenase-2 gene. J Clin Endocrinol Metab. 1999;84(9):3364–3377. [DOI] [PubMed] [Google Scholar]
- 257. Fazleabas AT, Donnelly KM, Hild-Petito S, Hausermann HM, Verhage HG. Secretory proteins of the baboon (Papio anubis) endometrium: regulation during the menstrual cycle and early pregnancy. Hum Reprod Update. 1997;3(6):553–559. [DOI] [PubMed] [Google Scholar]
- 258. Hausermann HM, Donnelly KM, Bell SC, Verhage HG, Fazleabas AT. Regulation of the glycosylated beta-lactoglobulin homolog, glycodelin [placental protein 14:(PP14)] in the baboon (Papio anubis) uterus. J Clin Endocrinol Metab. 1998;83(4):1226–1233. [DOI] [PubMed] [Google Scholar]
- 259. Jones RL, Critchley HO, Brooks J, Jabbour HN, McNeilly AS. Localization and temporal expression of prolactin receptor in human endometrium. J Clin Endocrinol Metab. 1998;83(1):258–262. [DOI] [PubMed] [Google Scholar]
- 260. Paiva P, Menkhorst E, Salamonsen L, Dimitriadis E. Leukemia inhibitory factor and interleukin-11: critical regulators in the establishment of pregnancy. Cytokine Growth Factor Rev. 2009;20(4):319–328. [DOI] [PubMed] [Google Scholar]
- 261. Gellersen B, Brosens J. Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J Endocrinol. 2003;178(3):357–372. [DOI] [PubMed] [Google Scholar]
- 262. Dimitriadis E, White CA, Jones RL, Salamonsen LA. Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update. 2005;11(6):613–630. [DOI] [PubMed] [Google Scholar]
- 263. Bahar Halpern K, Vana T, Walker MD. Paradoxical role of DNA methylation in activation of FoxA2 gene expression during endoderm development. J Biol Chem. 2014;289(34):23882–23892. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 264. Golson ML, Kaestner KH. Fox transcription factors: from development to disease. Development. 2016;143(24):4558–4570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 265. Turco MY, Gardner L, Hughes J, Cindrova-Davies T, Gomez MJ, Farrell L, Hollinshead M, Marsh SG, Brosens JJ, Critchley HO, Simons BD, Hemberger M, Koo BK, Moffett A, Burton GJ. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat Cell Biol. 2017;19(5):568–577. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 266. Boretto M, Cox B, Noben M, Hendriks N, Fassbender A, Roose H, Amant F, Timmerman D, Tomassetti C, Vanhie A, Meuleman C, Ferrante M, Vankelecom H. Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Development. 2017;144(10):1775–1786. [DOI] [PubMed] [Google Scholar]
- 267. Olalekan SA, Burdette JE, Getsios S, Woodruff TK, Kim JJ. Development of a novel human recellularized endometrium that responds to a 28-day hormone treatment. Biol Reprod. 2017;96(5):971–981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 268. Gnecco JS, Pensabene V, Li DJ, Ding T, Hui EE, Bruner-Tran KL, Osteen KG. Compartmentalized culture of perivascular stroma and endothelial cells in a microfluidic model of the human endometrium. Ann Biomed Eng. 2017;45(7):1758–1769. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 269. Dimitriadis E, Stoikos C, Stafford-Bell M, Clark I, Paiva P, Kovacs G, Salamonsen LA. Interleukin-11, IL-11 receptorα and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window. J Reprod Immunol. 2006;69(1):53–64. [DOI] [PubMed] [Google Scholar]
- 270. Hannan NJ, Paiva P, Meehan KL, Rombauts LJ, Gardner DK, Salamonsen LA. Analysis of fertility-related soluble mediators in human uterine fluid identifies VEGF as a key regulator of embryo implantation. Endocrinology. 2011;152(12):4948–4956. [DOI] [PubMed] [Google Scholar]
- 271. Boomsma CM, Kavelaars A, Eijkemans MJ, Lentjes EG, Fauser BC, Heijnen CJ, Macklon NS. Endometrial secretion analysis identifies a cytokine profile predictive of pregnancy in IVF. Hum Reprod. 2009;24(6):1427–1435. [DOI] [PubMed] [Google Scholar]
- 272. van der Gaast MH, Beier-Hellwig K, Fauser BC, Beier HM, Macklon NS. Endometrial secretion aspiration prior to embryo transfer does not reduce implantation rates. Reprod Biomed Online. 2003;7(1):105–109. [DOI] [PubMed] [Google Scholar]
- 273. Díaz-Gimeno P, Horcajadas JA, Martinez-Conejero JA, Esteban FJ, Alama P, Pellicer A, Simon C. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril. 2011;95(1):50–60, 60.e1–15. [DOI] [PubMed] [Google Scholar]
- 274. Gómez E, Ruíz-Alonso M, Miravet J, Simón C. Human endometrial transcriptomics: implications for embryonic implantation. Cold Spring Harb Perspect Med. 2015;5(7):a022996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 275. Dalton CF, Laird SM, Estdale SE, Saravelos HG, Li TC. Endometrial protein PP14 and CA-125 in recurrent miscarriage patients; correlation with pregnancy outcome. Hum Reprod. 1998;13(11):3197–3202. [DOI] [PubMed] [Google Scholar]
- 276. Garrido-Gomez T, Dominguez F, Quiñonero A, Diaz-Gimeno P, Kapidzic M, Gormley M, Ona K, Padilla-Iserte P, McMaster M, Genbacev O, Perales A, Fisher SJ, Simón C. Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology. Proc Natl Acad Sci USA. 2017;114(40):E8468–E8477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 277. Gargett CE, Schwab KE, Deane JA. Endometrial stem/progenitor cells: the first 10 years. Hum Reprod Update. 2016;22(2):137–163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 278. Salazar CA, Isaacson K, Morris S. A comprehensive review of Asherman’s syndrome: causes, symptoms and treatment options. Curr Opin Obstet Gynecol. 2017;29(4):249–256. [DOI] [PubMed] [Google Scholar]
- 279. Gargett CE, Nguyen HP, Ye L. Endometrial regeneration and endometrial stem/progenitor cells. Rev Endocr Metab Disord. 2012;13(4):235–251. [DOI] [PubMed] [Google Scholar]
- 280. Cervelló I, Santamaría X, Miyazaki K, Maruyama T, Simón C. Cell therapy and tissue engineering from and toward the uterus. Semin Reprod Med. 2015;33(5):366–372. [DOI] [PubMed] [Google Scholar]