DOI: 10.21451/1984-3143-AR888 Anim. Reprod., v.14, n.1, p.7-29, Jan./Mar. 2017 Pregnancy recognition signals in mammals: the roles of interferons and estrogens Fuller W. Bazer1,3, Guoyao Wu1, Greg A. Johnson2 1Departments of Animal Science and 2Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA. Abstract membranes). In primates, however, the menstrual cycle is uterine-independent as luteolytic PGF is produced Reproduction is a highly complex biological within the ovaries. During the peri-implantation period process requiring a dialogue between the developing of pregnancy, maternal recognition of pregnancy signals conceptus (embryo-fetus and associated placental from the conceptus to the maternal system are either membranes) and maternal uterus which must be antiluteolytic or luteotrophic. Antiluteolytic signals established during the peri-implantation period for prevent uterine release of luteolytic PGF while pregnancy recognition signaling and regulation of gene luteotrophic signals act directly on the CL to prevent expression by uterine epithelial and stromal cells. The luteolysis. The functional lifespan of the CL is uterus provide a microenvironment in which molecules controlled by the timing of release of PGF from the secreted by uterine epithelia or transported into the uterus and/or ovary, while maternal recognition of uterine lumen represent histotroph or the secretome pregnancy signals from the conceptus may act in either required for growth and development of the conceptus a paracrine or endocrine manner to prevent uterine and receptivity of the uterus to implantation by the and/or ovarian release of luteolytic PGF (Fig. 1). conceptus. Pregnancy recognition signaling as related to Following successful signaling for maternal recognition sustaining the functional lifespan of the corpora lutea and establishment of pregnancy, progesterone (P4) from (CL) which produce progesterone; the hormone of the CL and numerous hormones from the placenta are pregnancy essential for uterine functions that support required for maintenance of pregnancy and birth of implantation and placentation required for successful viable offspring. outcomes of pregnancy. It is within the peri- implantation period that most embryonic deaths occur in Corpus luteum (CL) formation and regression mammals due to deficiencies attributed to uterine functions or failure of the conceptus to develop Mammals may be spontaneous ovulators (e.g. appropriately, signal pregnancy recognition and/or ruminants, pigs, horses, and primates), induced undergo implantation and placentation. The endocrine ovulators (e.g., rabbit and cat) or spontaneous ovulators status of the pregnant female and her nutritional status are with induced CL (mice and rats). Except for primates, critical for successful establishment and maintenance of the estrous cycle is dependent on the uterine production pregnancy. The challenge is to understand the complexity of luteolytic PGF for functional (cessation of P4 of key mechanisms that are characteristic of successful production) and structural (luteal cell death) regression reproduction and to use that knowledge to enhance of the CL (Stouffer, 1988). In ruminants, luteolytic fertility and reproductive health of animals including pulses of PGF are released by uterine luminal (LE) and nonhuman primates. It is important to translate superficial glandular epithelia (sGE) that are expressing knowledge gained from studies of animals to address receptors for estrogens (ESR1) and oxytocin (OXTR), issues of fertility and reproductive health in humans. as well as prostaglandin synthase 2 (PTGS2), the rate limiting enzyme in synthesis of prostaglandins. The Keywords: Pregnancy recognition, interferon tau, uterine luteolytic mechanism requires sequential effects estrogen, prolactin, mammals of P4, estradiol (E2) and oxytocin (OXT) acting through their respective receptors on uterine LE/sGE to Introduction stimulate accumulation of phospholipids, expression of OXTR and release of oxytocin (OXT)-induced The endocrinology of recurring luteolytic pulses of PGF (Spencer et al., 2004). At onset estrous/menstrual cycles and pregnancy in primates, of estrus (day 0), estrogens from mature Graafian ruminants, swine, horses, cats, dogs and rodents follicles increase expression of ESR1, progesterone includes hormonal signaling for maternal recognition of receptor (PGR) and OXTR, respectively. During pregnancy and the endocrinology of pregnancy. The diestrus, P4 from the CL: 1) stimulates accumulation of estrous cycle of subprimate species is uterine- phospholipids in LE/sGE that liberates arachidonic acid dependent, because the uterus produces prostaglandin for synthesis and secretion of PGF; 2) acts via PGR to F2α (PGF), the luteolytic hormone responsible for “block” expression of ESR1 and OXTR in uterine functional and structural regression of the ovarian LE/sGE for 10 to 12 days; and 3) down-regulates PGR corpus luteum (CL) in the absence of an appropriate expression by LE/sGE between days 11 and 13 to maternal recognition of pregnancy signal from the release the “P4 block” to expression of ESR1 and then conceptus (embryo and its extra-embryonic OXTR necessary for OXT-induced release of luteolytic _________________________________________ 3Corresponding author: [email protected] Received: August 16, 2016 Accepted: September, 9 2016 Bazer et al. Pregnancy recognition signals. pulses of PGF required for regression of the CL. The Pregnancy recognition signals for maintenance of CL promoter region of the ovine OXTR gene contains Sp1 response elements that mediate responsiveness to Pregnancy is established and maintained in liganded ESR1 that increases transcription of OXTR in subprimate mammals in response to signaling from the uterine LE/sGE. Continuous exposure of the uterus to conceptus and/or anterior pituitary to the uterus and/or P4 for 10 to 12 days down-regulates PGR in CL to exert antiluteolytic effects that prevent uterine endometrial LE/sGE to allow a rapid increase in ESR1 release of PGF or act as a luteotrophic signal to directly in those cells beginning on day 13 and OXTR increase stimulate development and function of the CL. from days 14 to 17 in cyclic ewes. The mechanism Although the luteolytic mechanism in primates remains responsible for P4-induced down-regulation of PGR is unclear, chorionic gonadotrophin beta subunit (CGB) is not known. In ewes, pulsatile release of OXT from the the luteotrophin required to extend lifespan of the CL posterior pituitary gland and CL induces coordinate and it is produced by primate blastocysts during the release of luteolytic pulses of PGF from uterine LE/sGE peri-implantation period to signal maternal recognition on days 15 and 16 to induce CL regression. of pregnancy. Figure 1. Interferon tau (IFNT) and estradiol in concert with prolactin (PRL) are antiluteolytic pregnancy recognition signals from trophectoderm cells of ruminant and porcine species whereas chorionic beta (CGB) and lactogenic hormones such as PRL and placental lactogens act directly on the corpus luteum as luteotrophic signals. In each case, one or more functional corpora lutea are maintained to produce progesterone which is required for establishment and maintenance of pregnancy (see Bazer et al., 2009b). Luteinizing hormone (LH), chorionic gonadotophin beta both bind to and transactivate the LH/CG receptor chain (CGB) and LH/CG Receptor (LHCGR; see Rao, (LHCGR), they are unique and confer different 2001; Ziecik et al., 2007) biological activities and immunological identities. Binding of LH or CGB to LHCGR activates a G protein LH, a dimeric glycoprotein, shares a common bound to the cytoplasmic domain of the LHCGR which alpha subunit with follicle stimulating hormone (FSH), detaches from LHCGR to activate the cAMP system thyroid stimulating hormone (TSH) and CGB. However, and cAMP-dependent protein kinases (protein kinase although the beta subunit of LH (LHB) and CG (CGB) A). The PKAs are tetramers with two regulatory and 8 Anim. Reprod., v.14, n.1, p.7-29, Jan./Mar. 2017 Bazer et al. Pregnancy recognition signals. two catalytic subunits. Upon binding cAMP by the (fibroblast growth factor receptor 2 splice variant or regulatory units, the catalytic units are released to FGFR2IIIb) and HGF (met proto-oncogene or MET). In initiate phosphorylation of proteins that then activate sheep and perhaps other ruminants, a select set of genes genes that effect biological responses. LH acts on expressed by uterine LE/sGE are P4-induced and IFNT mature Graffian follicles to induce ovulation and stimulated. The uterine LE/sGE do not express PGR or luteinization of theca and granulosa cells that form the signal transducers and activators of transcription CL and produce P4. Basal output of LH from the (STAT1). Therefore, a fundamental unanswered anterior pituitary is permissive for maintenance of CL question is whether actions of progestamedins and IFNs function in most species. However, CGB from on uterine LE/sGE involves non-classical cell signaling trophectoderm/chorion is the maternal recognition of pathways independent of PGR and STAT1, such as pregnancy signal in primates. In addition, LH and CGB mitogen activated protein kinases (MAPK) and bind LHCGR expressed in the myometrium, phosphoinositide-3 kinase (PI3K; Plantanias, 2005). endometrium, oviduct, broad ligament, uterine blood Indeed, IFNT activates cell signaling pathways to vessels, cervix, mammary gland, placenta and umbilical differentially affect gene expression