Mechanistic mammalian target of rapamycin (MTOR) cell signaling: Effects of select nutrients and secreted phosphoprotein 1 on development of mammalian conceptuses

Bazer, Fuller W.,Song, Gwonhwa,Kim, Jinyoung,Erikson, David W.,Johnson, Greg A.,Burghardt, Robert C.,Gao, Haijun,Carey Satterfield, M.,Spencer, Thomas E.,Wu, Guoyao Elsevier 2012 Molecular and cellular endocrinology Vol.354 No.1

<P><B>Highlights</B></P><P>► Uterine epithelia secrete proteins and transport nutrients for conceptus development. ► Arginine and secreted phosphoprotein 1 (SPP1) activate MTOR cell signaling. ► Arginine metabolism to nitric oxide and polyamines stimulates conceptus growth. ► SPP1 induces focal adhesions between trophectoderm and uterine epithelia. ► Arginine and SPP1 stimulate conceptus development, implantation and pregnancy.</P> <P><B>Abstract</B></P><P>Morphological differentiation of uterine glands in mammals is a postnatal event vulnerable to adverse effects of endocrine disruptors. Exposure of ewe lambs to a progestin from birth to postnatal day 56 prevents development of uterine glands and, as adults, the ewes are unable to exhibit estrous cycles or maintain pregnancy. Uterine epithelia secrete proteins and transport nutrients into the uterine lumen necessary for conceptus development, pregnancy recognition signaling and implantation, including arginine and secreted phosphoprotein 1 (SPP1). Arginine can be metabolized to nitric oxide and to polyamines or act directly to activate MTOR cell signaling to stimulate proliferation, migration, and mRNA translation in trophectoderm cells. SPP1 binds αvβ3 and α5β1 integrins and induces focal adhesion assembly, adhesion and migration of conceptus trophectoderm cells during implantation. Thus, arginine and SPP1 mediate growth, migration, cytoskeletal remodeling and adhesion of trophectoderm essential for pregnancy recognition signaling and implantation.</P>

Pregnancy Recognition Signaling for Establishment and Maintenance of Pregnancy

Bazer, Fuller W. The Korean Society of Animal Reproduction 1999 Reproductive & developmental biology Vol.23 No.4

Interferon tau (IFN$\tau$), the pregnancy recognition signal in ruminants, suppresses transcription of the estrogen receptor (ER) gene in the endometrial luminal (LE) and superficial glandular epithelium (sGE) to prevent oxytocin receptor (OTR) expression and pulsatile release of luteolytic prostaglandin $F_{2{\alpha}}$ (PGF), Interferon regulatory factors one (IRF-l) and two (IRF-2) are transcription factors induced by IFN$\tau$ that activate and silence gene expression, respectively. Available results suggest that IFN$\tau$ acts directly on LE and sGE during pregnancy to induce sequentially IRF-l and then IRF-2 gene expression to silence transcription of ER and OTR genes, block the luteolytic mechanism to maintenance a functional corpus luteum (CL) and, signal maternal recognition of pregnancy. The theory for maternal recognition of pregnancy in pigs is that the uterine endometrium of cyclic gilts secretes PGF in an endocrine direction, toward the uterine vasculature for transport to the CL to exert its luteolytic effect. However, in pregnant pigs, estrogens secreted by the conceptuses are responsible, perhaps in concert with effects of prolactin and calcium, for exocrine secretion of PGF into the uterine lumen where it is sequestered to exert biological effects and / or be metabolized to prevent luteolysis.

Novel pathways for implantation and establishment and maintenance of pregnancy in mammals

Bazer, F. W.,Wu, G.,Spencer, T. E.,Johnson, G. A.,Burghardt, R. C.,Bayless, K. Oxford University Press 2010 Molecular human reproduction Vol.16 No.3

Roles of Conceptus Secretory Proteins in Establishment and Maintenance of Pregnancy in Ruminants

Bazer, Fuller W.,Song, Gwon-Hwa,Thatcher, William W. Asian Australasian Association of Animal Productio 2012 Animal Bioscience Vol.25 No.1

Reproduction in ruminant species is a highly complex biological process requiring a dialogue between the developing conceptus (embryo-fetus and associated placental membranes) and maternal uterus which must be established during the peri-implantation period for pregnancy recognition signaling and regulation of gene expression by uterine epithelial and stromal cells. The uterus provide a microenvironment in which molecules secreted by uterine epithelia and transported into the uterine lumen represent histotroph, also known as the secretome, that are required for growth and development of the conceptus and receptivity of the uterus to implantation by the elongating conceptus. Pregnancy recognition signaling as related to sustaining the functional lifespan of the corpora lutea, is required to sustain the functional life-span of corpora lutea for production of progesterone which is essential for uterine functions supportive of implantation and placentation required for successful outcomes of pregnancy. It is within the peri-implantation period that most embryonic deaths occur in ruminants due to deficiencies attributed to uterine functions or failure of the conceptus to develop appropriately, signal pregnancy recognition and/or undergo implantation and placentation. The endocrine status of the pregnant ruminant and her nutritional status are critical for successful establishment and maintenance of pregnancy. The challenge is to understand the complexity of key mechanisms that are characteristic of successful reproduction in humans and animals and to use that knowledge to enhance fertility and reproductive health of ruminant species in livestock enterprises.

Select nutrients, progesterone, and interferon tau affect conceptus metabolism and development

Bazer, Fuller W,Kim, Jingyoung,Song, Gwonhwa,Ka, Hakhyun,Tekwe, Carmen D,Wu, Guoyao Blackwell Publishing Inc 2012 Annals of the New York Academy of Sciences Vol.1271 No.1

<P>Interferon tau (IFNT), a novel multifunctional type I interferon secreted by trophectoderm, is the pregnancy recognition signal in ruminants that also has antiviral, antiproliferative, and immunomodulatory bioactivities. IFNT, with progesterone, affects availability of the metabolic substrate in the uterine lumen by inducing expression of genes for transport of select nutrients into the uterine lumen that activate mammalian target of rapamycin (mTOR) cell signaling responsible for proliferation, migration, and protein synthesis by conceptus trophectoderm. As an immunomodulatory protein, IFNT induces an anti-inflammatory state affecting metabolic events that decrease adiposity and glutamine:fructose-6-phosphate amidotransferase 1 activity, while increasing insulin sensitivity, nitric oxide production by endothelial cells, and brown adipose tissue in rats. This short review focuses on effects of IFNT and progesterone affecting transport of select nutrients into the uterine lumen to stimulate mTOR cell signaling required for conceptus development, as well as effects of IFNT on the immune system and adiposity in rats with respect to its potential therapeutic value in reducing obesity.</P>

Pregnancy Recognition Signaling for Establishment and Maintenance of Pregnancy

Fuller W. Bazer 한국동물생명공학회(구 한국동물번식학회) 1999 Reproductive & developmental biology Vol.23 No.4

Contributions of an animal scientist to reproductive biology.

Society for the Study of Reproduction [etc.] 2011 BIOLOGY OF REPRODUCTION Vol.85 No.2

<P>I became interested in biology as an undergraduate in a premedical curriculum but developed a passion for the field of reproductive biology because of a course in physiology of reproduction taken to meet requirements for admission to veterinary school. My career path changed, and I entered graduate school, obtained the Ph.D., and have enjoyed an academic career as a reproductive biologist conducting research in uterine biology and pregnancy in animal science departments at the University of Florida and at Texas A&M University. However, I have never allowed academic boundaries to interfere with research and graduate education as that is contrary to collegiality, the cornerstone of great universities. I consider that my major contributions to science include 1) identification of proteins secreted by cells of the uterine endometrium that are critical to successful establishment and maintenance of pregnancy; 2) discovery of steroids and proteins required for pregnancy recognition signaling and their mechanisms of action in pigs and ruminant species; 3) investigation of fetal-placental development and placental transport of nutrients, including water and electrolytes; 4) identification of linkages between nutrition and fetal-placental development; 5) defining aspects of the endocrinology of pregnancy; and 6) contributing to efforts to exploit the therapeutic value of interferon tau, particularly for treatment of autoimmune diseases. My current studies are focused on the role of select nutrients in the uterine lumen, specifically amino acids and glucose, that affect development and survival of the conceptus and translation of mRNAs and, with colleagues at Seoul National University, gene expression by the avian reproductive tract at key periods postovulation. Another goal is to understand stromal-epithelial cell signaling, whereby progesterone and estrogen act via uterine stromal cells that express receptors for sex steroids to stimulate secretion of growth factors (e.g., fibroblast growth factors and hepatocyte growth factor) that, in turn, regulate functions of uterine epithelial cells and conceptus trophectoderm.</P>

Uterine Adenogenesis and Pregnancy: Multiple Roles for Foxa2 in Mice Foxa2 is required for uterine gland development and pregnancy in mice

SOCIETY FOR THE STUDY OF REPRODUCTION 2010 BIOLOGY OF REPRODUCTION Vol.83 No.3

Epidermal growth factor stimulates proliferation and migration of porcine trophectoderm cells through protooncogenic protein kinase 1 and extracellular-signal-regulated kinases ½ mitogen-activated protein kinase signal transduction cascades during early

Jeong, W.,Kim, J.,Bazer, F.W.,Song, G. North-Holland 2013 Molecular and cellular endocrinology Vol.381 No.1

For successful implantation and establishment of early epitheliochorial placentation, porcine conceptuses require histotroph, including nutrients and growth factors, secreted by or transported into the lumen of the uterus. Epidermal growth factor (EGF), an essential component of histotroph, is known to have potential growth-promoting activities on the conceptus and uterine endometrium. However, little is known about its effects to transactivate cell signaling cascades responsible for proliferation, growth and differentiation of conceptus trophectoderm. In the present study, therefore, we determined that EGFR mRNA and protein were abundant in endometrial luminal and glandular epithelia, stratum compactum stroma and conceptus trophectoderm on days 13-14 of pregnancy, but not in any other cells of the uterus or conceptus. In addition, primary porcine trophectoderm (pTr) cells treated with EGF exhibited increased abundance of phosphorylated (p)-AKT1, p-ERK½ MAPK and p-P90RSK over basal levels within 5min, and effect that was maintained to between 30 and 120min. Immunofluorescence microscopy revealed abundant amounts of p-ERK½ MAPK and p-AKT1 proteins in the nucleus and, to a lesser extent, in the cytoplasm of pTr cells treated with EGF as compared to control cells. Furthermore, the abundance of p-AKT1 and p-ERK½ MAPK proteins was inhibited in control and EGF-treated pTr cells transfected with EGFR siRNA. Compared to the control siRNA transfected pTr cells, pTr cells transfected with EGFR siRNA exhibited an increase in expression of IFND and TGFB1, but there was no effect of expression of IFNG. Further, EGF stimulated proliferation and migration of pTr cells through activation of the PI3K-AKT1 and ERK½ MAPK-P90RSK cell signaling pathways. Collectively, these results support the hypothesis that EGF coordinately activates multiple cell signaling pathways critical to proliferation, migration and survival of trophectoderm cells that are critical to development of porcine conceptuses during implantation and placentation.

Stem cell factor-induced AKT cell signaling pathway: Effects on porcine trophectoderm and uterine luminal epithelial cells

Jeong, Wooyoung,Jung, Seoungo,Bazer, Fuller W.,Kim, Jinyoung Elsevier 2017 General and comparative endocrinology Vol.250 No.-

<P><B>Abstract</B></P> <P>Stem cell factor (SCF) is a multipotent growth factor that elicits diverse biological actions in various aspects of embryogenesis and animal development. The aim of the present study was to assess SCF-induced intracellular signaling and cellular activities in porcine trophectoderm (pTr) and uterine luminal epithelial (pLE) cells which are well known as useful to elucidate developmental events. SCF induced abundances of p-AKT, p-P70RSK and RPS6 proteins in pTr cells reached to their maximum, and then returned to basal levels by 120min. In pLE cells, SCF induced protracted effect to increase AKT phosphorylation which was well correlated with the time course for P70RSK and RPS6 phosphorylation. LY294002 (an inhibitor of AKT) decreased SCF-induced p-AKT, p-P70RSK and p-RPS6 proteins. Also, immunofluorescence analyses revealed that p-RPS6 was abundant within the cytoplasm of SCF-treated cells, but p-RPS6 was present only at basal levels in cells treated with LY294002. In the presence of LY294002, both SCF-stimulated transient and sustained AKT phosphorylation were inhibited in pLE cells. Furthermore, SCF increased migration of pTr and pLE cells, but LY294002 significantly reduced this effect of SCF. In conclusion, results of the present study suggest that SCF secreted by the endometrium induces autocrine/paracrine signaling responses that stimulate migration of pTr and pLE cells through activation of the AKT cell signaling pathway. Those results support the hypothesis that SCF is a critical regulatory factor for conceptus development and implantation during pregnancy in pigs.</P> <P><B>Highlights</B></P> <P> <UL> <LI> SCF transcripts increase in endometrium during early pregnancy. </LI> <LI> SCF is a strong inducer of AKT activation in pTr and pLE cells. </LI> <LI> SCF-stimulated AKT activates P70RSK and RPS6 proteins in pTr cells. </LI> <LI> SCF induces transient and long-lasting activation of AKT cascade in pLE cells. </LI> <LI> SCF has stimulatory effect on cell migration through activation of PI3K/AKT cascade. </LI> </UL> </P>