HOTAIR is a long intervening non-coding RNA (lincRNA) that associates with the Polycomb Repressive Complex 2 (PRC2) and overexpression is correlated with poor survival for breast, colon and liver cancer patients. In this study, we show that HOTAIR expression is increased in pancreatic tumors compared to non-tumor tissue and is associated with more aggressive tumors. Knockdown of HOTAIR (siHOTAIR) by RNA interference shows that HOTAIR plays an important role in pancreatic cancer cell invasion and as reported in other cancer cell lines. In contrast, HOTAIR knockdown in Panc1 and L3.6pL pancreatic cancer cells that overexpress this lincRNA decreased cell proliferation, altered cell cycle progression, and induced apoptosis, demonstrating an expanded function for HOTAIR in pancreatic cancer cells compared to other cancer cell lines. Results of gene array studies showed that there was minimal overlap between HOTAIR-regulated genes in pancreatic vs. breast cancer cells and HOTAIR uniquely suppressed several interferon-related genes and gene sets related to cell cycle progression in pancreatic cancer cells and tumors. Analysis of selected genes suppressed by HOTAIR in Panc1 and L3.6 pL cells showed by knockdown of EZH2 and chromatin immunoprecipitation assays that HOTAIR-mediated gene repression was both PRC2-dependent and -independent. HOTAIR knockdown in L3.6pL cells inhibited tumor growth in mouse xenograft model, further demonstrating the pro-oncogenic function of HOTAIR in pancreatic cancer.

All mammalian uteri contain endometrial glands that synthesize or transport and secrete substances essential for survival and development of the conceptus (embryo/fetus and associated extraembryonic membranes). In rodents, uterine secretory products of the endometrial glands are unequivocally required for establishment of uterine receptivity and conceptus implantation. Analyses of the ovine uterine gland knockout model support a primary role for endometrial glands and, by default, their secretions in peri-implantation conceptus survival and development. Uterine adenogenesis is the process whereby endometrial glands develop. In humans, this process begins in the fetus, continues postnatally, and is completed during puberty. In contrast, endometrial adenogenesis is primarily a postnatal event in sheep, pigs, and rodents. Typically, endometrial adenogenesis involves differentiation and budding of glandular epithelium from luminal epithelium, followed by invagination and extensive tubular coiling and branching morphogenesis throughout the uterine stroma to the myometrium. This process requires site-specific alterations in cell proliferation and extracellular matrix (ECM) remodeling as well as paracrine cell-cell and cell-ECM interactions that support the actions of specific hormones and growth factors. Studies of uterine development in neonatal ungulates implicate prolactin, estradiol-17 beta, and their receptors in mechanisms regulating endometrial adenogenesis. These same hormones appear to regulate endometrial gland morphogenesis in menstruating primates and humans during reconstruction of the functionalis from the basalis endometrium after menses. In sheep and pigs, extensive endometrial gland hyperplasia and hypertrophy occur during gestation, presumably to provide increasing histotrophic support for conceptus growth and development. In the rabbit, sheep, and pig, a servomechanism is proposed to regulate endometrial gland development and differentiated function during pregnancy that involves sequential actions of ovarian steroid hormones, pregnancy recognition signals, and lactogenic hormones from the pituitary or placenta. That disruption of uterine development during critical organizational periods can alter the functional capacity and embryotrophic potential of the adult uterus reinforces the importance of understanding the developmental biology of uterine glands. Unexplained high rates of peri-implantation embryonic loss in humans and livestock may reflect defects in endometrial gland morphogenesis due to genetic errors, epigenetic influences of endocrine disruptors, and pathological lesions.

Uterine receptivity to implantation of blastocysts in mammals includes hatching from zona pellucida, precontact with uterine luminal (LE) and superficial glandular (sGE) epithelia and orientation of blastocyst, apposition between trophectoderm and uterine LE and sGE, adhesion of trophectoderm to uterine LE/sGE, and, in some species, limited or extensive invasion into the endometrial stroma and induction of decidualization of stromal cells. These peri-implantation events are prerequisites for pregnancy recognition signaling, implantation, and placentation required for fetal-placental growth and development through the remainder of pregnancy. Although there is a range of strategies for implantation in mammals, a common feature is the requirement for progesterone (P 4 ) to downregulate expression of its receptors in uterine epithelia and P 4 prior to implantation events. P 4 then mediates its effects via growth factors expressed by stromal cells in most species; however, uterine luminal epithelium may express a growth factor in response to P 4 and/or estrogens in species with a true epitheliochorial placenta. There is also compelling evidence that uterine receptivity to implantation involves temporal and cell-specific expression of interferon (IFN)-stimulated genes that may be induced directly by an IFN or induced by P 4 and stimulated by an IFN. These genes have many roles including nutrient transport, cellular remodeling, angiogenesis and relaxation of vascular tissues, cell proliferation and migration, establishment of an antiviral state, and protection of conceptus tissues from challenges by the maternal immune cells.

Uterine receptivity to implantation varies among species, and involves changes in expression of genes that are coordinate with attachment of trophectoderm to uterine lumenal and superficial glandular epithelia, modification of phenotype of uterine stromal cells, silencing of receptors for progesterone and estrogen, suppression of genes for immune recognition, alterations in membrane permeability to enhance conceptus-maternal exchange of factors, angiogenesis and vasculogenesis, increased vascularity of the endometrium, activation of genes for transport of nutrients into the uterine lumen, and enhanced signaling for pregnancy recognition. Differential expression of genes by uterine epithelial and stromal cells in response to progesterone, glucocorticoids, prostaglandins and interferons may influence uterine receptivity to implantation in mammals. Uterine receptivity to implantation is progesterone-dependent; however, implantation is preceded by loss of expression of receptors for progesterone (PGR) so that progesterone most likely acts via PGR-positive stromal cells throughout pregnancy. Endogenous retroviruses expressed by the uterus and/or blastocyst also affect implantation and placentation in various species. Understanding the roles of the variety of hormones, growth factors and endogenous retroviral proteins in uterine receptivity for implantation is essential to enhancing reproductive health and fertility in humans and domestic animals.

Osteopontin (OPN) is an acidic member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of extracellular matrix proteins/cytokines that undergoes extensive posttranslational modification, including phosphorylation, glycosylation, and cleavage, yielding molecular mass variants ranging in size from 25 to 75 kDa. The result is a versatile protein(s) with multiple functions arising from its role as a mediator of cell-cell and cell-extracellular matrix (ECM) communication that encompass both normal and tumorigenic developmental processes, immunological responses during inflammation and wound healing, and biomineralization. Studies in primates, pigs, sheep, and rodents have revealed that OPN is a major constituent of the uterine-placental microenvironment with influence as 1) a component of histotroph required for adhesion and signal transduction at the uterine-placental interface throughout pregnancy, 2) a gene product expressed by uterine stroma contributing to a decidualization-like transformation that correlates with the degree of conceptus invasiveness, and 3) a product of resident uterine and placental immune cells that may regulate their behavior and cytokine production. This minireview summarizes information regarding uterine and placental expression of OPN that has accumulated over the past 15 yr, and we briefly describe structural/functional properties of this protein that are likely relevant to its role(s) during pregnancy. Comparative studies have offered insights into the potential hormonal/cytokine, cellular, and molecular mechanisms underlying OPN-mediated adhesion, remodeling, and cell-cell/cell-ECM communication within the uterus and placenta. OPN has the potential to profoundly impact pregnancy, and investigators are now challenged to focus on the mechanistic nature of the functions of this multifaceted and major component of the uterine-placental microenvironment.

Trials of GDNF in Parkinson’s disease have yielded inconsistent results. In a randomised controlled trial, Whone et al. administer GDNF using a paradigm designed to optimize delivery to the putamen. [ 18 F]DOPA PET reveals putamen-wide uptake, but GDNF does not differ from placebo in its effects on motor function.

Progesterone is unequivocally required for maternal support of conceptus (embryo/fetus and associated extraembryonic membranes) survival and development. In cyclic sheep, progesterone is paradoxically involved in suppressing and then initiating development of the endometrial luteolytic mechanism. In cyclic and pregnant sheep, progesterone negatively autoregulates progesterone receptor (PR) gene expression in the endometrial luminal (LE) and superficial glandular epithelium (GE). In cyclic sheep, PR loss is closely followed by increases in epithelial estrogen receptor (ERalpha) and then oxytocin receptor (OTR), allowing oxytocin to induce uterine release of luteolytic prostaglandin F2alpha pulses. In pregnant sheep, the conceptus produces interferon tau (IFNtau) that acts on the endometrium to inhibit transcription of the ERalpha gene and thus development of the endometrial luteolytic mechanism. After Day 13 of pregnancy, the endometrial epithelia do not express the PR, whereas the stroma and myometrium remain PR positive. The absence of PR in the endometrial GE is required for onset of differentiated function of the glands during pregnancy. The sequential, overlapping actions of progesterone, IFNtau, placental lactogen (PL), and growth hormone (GH) comprise a hormonal servomechanism that regulates endometrial gland morphogenesis and terminal differentiated function during gestation. In pigs, estrogen, the pregnancy-recognition signal, increases fibroblast growth factor 7 (FGF-7) expression in the endometrial LE that, in turn, stimulates proliferation and differentiated functions of the trophectoderm, which expresses the receptor for FGF-7. Strategic manipulation of these physiological mechanisms may offer therapeutic schemes to improve uterine capacity, conceptus survival, and reproductive health of domestic animals and humans.

The present review highlights new information on pregnancy recognition and conceptus development and implantation in sheep with respect to regulation by progesterone, interferons and endogenous retroviruses. After formation of the corpus luteum, progesterone acts on the endometrium and stimulates blastocyst growth and elongation to a filamentous conceptus (embryo/fetus and associated extra-embryonic membranes). The envelope of endogenous retroviruses related to Jaagsiekte sheep retroviruses appears to intrinsically regulate mononuclear trophectoderm cell proliferation and differentiation into trophoblast giant binucleate cells. The mononuclear trophectoderm cells of elongating sheep conceptuses secrete interferon-tau, which acts on the endometrium to prevent development of the luteolytic mechanism by inhibiting transcription of the gene for the oestrogen receptor alpha in the luminal and superficial ductal glandular epithelia. These actions prevent oestrogen-induced transcription of the oxytocin receptor gene and, therefore, oxytocin-induced luteolytic pulses of prostaglandin F2alpha. Progesterone down regulation of its receptors in luminal and glandular epithelia correlates temporally with a reduction in anti-adhesive mucin land induction of secreted galectin 15 (LGALSI5) and secreted phosphoprotein 1, which are proposed to regulate trophectoderm proliferation and adhesion. Interferon-c acts on the endometrial lumenal epithelium to induce WNT7A and to stimulate LGALS 15, cathepsin L and cystatin C, which are candidate regulators of conceptus development and implantation. The number of potential contributors to maternal recognition and establishment of pregnancy continues to grow and this highlights our limited appreciation of the complexity of the key molecules and signal transduction pathways that intersect during these key developmental processes. The goal of improving reproductive efficiency by preventing embryonic losses that occur during the peri-implantation period of pregnancy in domestic ruminants provides the challenge to increase our knowledge of endometrial function and conceptus development.