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

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>

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.

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.

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

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

Naringenin induces mitochondria-mediated apoptosis and endoplasmic reticulum stress by regulating MAPK and AKT signal transduction pathways in endometriosis cells

Park, Sunwoo,Lim, Whasun,Bazer, Fuller W,Song, Gwonhwa Oxford University Press 2017 Molecular human reproduction Vol.23 No.12

Fibroblast growth factor 4-induced migration of porcine trophectoderm cells is mediated via the AKT cell signaling pathway

Jeong, W.,Lee, J.,Bazer, F.W.,Song, G.,Kim, J. North-Holland 2016 Molecular and cellular endocrinology Vol.419 No.-

<P>During early pregnancy, a well-coordinated communication network between the conceptus and maternal uterus is especially crucial in pigs in which there is a protracted pre-attachment phase prior to implantation. This network is regulated by an astonishing number of molecules such as growth factors. Fibroblast growth factor 4 (FGF4) is a multipotent growth factor that elicits diverse biological actions on various types of cells and tissues. In pigs, FGF4 and its receptors are expressed in the uterine endometrium and conceptus during early pregnancy, but less is known about the FGF4-mediated regulation of conceptus growth during peri-implantation period of pregnancy. Therefore, the aims of the present study were to investigate: 1) expression of endometrial FGF4 mRNA during early pregnancy; 2) up-regulation of FGF receptor expression in porcine trophectoderm (pTr) cells in response to FGF4; and 3) FGF-induced intracellular signaling and cellular activities in pTr cells. In vitro cultured pTr cells incubated with different concentrations of recombinant FGF4 (0-50 ng/ml) responded with a dose-dependent increase in AKT phosphorylation of 2.9-fold at 20 ng/ml FGF4. Within 30 min after treatment with 20 ng/ml FGF4, the abundances of p-AKT, p-P90RSK and p-RPS6 proteins increased 2.1-, 5.2- and 3.2-fold, respectively, and then returned to basal levels by 120 min. To ensure that the stimulatory effect of FGF4 on AKT signaling was p-AKT-dependent, pTr cells were pre-incubated with an AKT inhibitor (LY294002) for 1 h prior to FGF4 treatment. 20 mu M of LY294002 decreased FGF4-induced p-AKT, p-P9ORSK and p-RPS6 proteins. Immunofluorescence analyses revealed that p-RPS6 proteins were abundant within the cytoplasm of FGF4-treated cells, but present at basal levels in the presence of LY294002. Furthermore, FGF4 increased migration of pTr cells and LY294002 significantly reduced this effect. Results of the present study suggest that activation of the FGF receptor(s) on trophectoderm cells by FGF4 secreted by conceptus/endometrium transduces its signal through the phosphatidylinositol 3-kinase (PI3K)/AKT pathway which is linked to migration of trophectoderm cells that is critical to development of the porcine conceptus. (C) 2015 Elsevier Ireland Ltd. All rights reserved.</P>