Select nutrients and their effects on conceptus development in mammals

Abstract

The dialogue between the mammalian conceptus (embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the critical peri-implantation period of pregnancy when the stage is set for implantation and placentation that precedes fetal development. Uterine epithelial cells secrete and/or transport a wide range of molecules, including nutrients, collectively referred to as histotroph that are transported into the fetal-placental vascular system to support growth and development of the conceptus. The availability of uterine-derived histotroph has long-term consequences for the health and well-being of the fetus and the prevention of adult onset of metabolic diseases. Histotroph includes numerous amino acids, but arginine plays a particularly important role as a source of nitric oxide and polyamines required for fetal-placental development in rodents, swine and humans through mechanisms that remain to be fully elucidated. Mechanisms whereby arginine regulates expression of genes via the mechanistic target of rapamycin cell signaling pathways critical to conceptus development, implantation and placentation are discussed in detail in this review.

Keywords: Amino acids; Conceptus development; Interferon tau; Pregnancy; Secreted phosphoprotein 1; Trophectoderm.

Fig. 1

Interferon tau (IFNT) acts, with progesterone (P4) being permissive, to signal pregnancy recognition by silencing expression of estrogen receptor alpha (ESR1) and oxytocin receptor (OXTR) which abrogates the mechanism for oxytocin-induced pulsatile release of prostaglandin F_2a. Therefore the ovarian corpora lutea remain functional and produce P4, the hormone of pregnancy. Interferon tau and P4-induced progestamedins act on uterine glandular epithelia for secretion of uteroferrin that stimulates erythropoiesis, while IFNT and P4-induced progestamedins act via uterine luminal epithelium and superficial glandular epithelia to increase transport of arginine to conceptus trophectoderm and uterine epithelia for metabolism to nitric oxide and polyamines essential for conceptus growth and development. SLC7A1 = solute carrier family member 7; GE = glandular epithelia.

Fig. 2

The peri-implantation of pregnancy in ewes in marked by a rapid transition of hatched blastocysts from spherical to tubular and filamentous forms in response to proteins and select nutrients secreted and/or transported into the uterine lumen. The trophectoderm cells and extra-embryonic endoderm cells undergo proliferation, migration, and cytoskeletal changes to elongate which is critical for secreting interferon tau (IFNT) the signal for pregnancy recognition, as well as implantation. Arginine and secreted phosphoprotein 1 are important for stimulating growth and development of ovine and porcine conceptuses.

Fig. 3

The uterine microenvironment of histotroph includes various molecules that are secreted or transported into the uterine lumen to stimulate growth and development of the conceptus during the peri-implantation period. Interferon tau (IFNT) induces interferon regulatory factor 2 in uterine luminal epithelium (LE) and superficial glandular (sGE) epithelia which prevents their expression of classical interferon stimulated genes (ISGs). Rather, uterine LE/sGE express genes for nutrient transporters and other genes critical for growth and development of the conceptus. The uterine glandular epithelium (GE) and stromal cells do express classical ISGs.

Fig. 4

Model for induction of cell signaling for proliferation, migration, adhesion, and cytoskeletal remodeling of conceptuses via MTORC1 and MTORC2 signaling cascade. AKT1 = proto-oncogenic protein kinase 1; FAK = focal adhesion kinase; PDK1 = phosphoinositide-dependent protein kinase 1; MTOR = mechanistic target of rapamycin; RAPTOR = regulatory-associated protein of MTOR; RICTOR = rapamycin-insensitive companion of MTOR; IGF2 = insulin-like growth factor 2; type I IGF2 = type I insulin-like growth factor receptor; ILK = integrin-linked kinases; IRS1 = insulin receptor substrate 1; PKC = protein kinase C; SGK = serum/glucocorticoid-regulated kinase; MLST8 = mammalian lethal with SEC13 protein 8; PRAS40 = proline-rich Akt/PKB substrate 40 kDa; DEPTOR = DEP domain-containing MTOR-interacting protein; MSIN1 = mammalian stress-activated MAP kinase interacting protein 1; PROTOR = protein observed with RICTOR; NCK2 = non-catalytic region of tyrosine kinase, beta; NO = nitric oxide; NOS3 = nitric oxide synthase 3; ODC1 = ornithine decarboxylase; PI3K = phosphatidylinositol 3-kinase; LIMS1 = LIM and senescent cell antigen-like domains 1; S6K = S6 kinase; SPP1 = secreted phosphoprotein 1; MTORC= mammalian target of rapamycin complex; TSC = tuberous sclerosis ; 4E-BP = eIF4E binding proteins.

Fig. 5

Arginine is transported into trophectoderm cells by the solute carrier family member 7 (SLC7A1) where it can be converted to nitric oxide (NO) by nitric oxide synthase 3 (NOS3) or arginine can be converted to ornithine by arginase and then ornithine is converted to putrescine by ornithine decarboxylase (ODC1). However, the sheep conceptus can also convert arginine to agmatine via arginine decarboxylase and agmatine can be converted to putrescine by agmatinase. ADC = arginine decarboxylase; BH4 = tetrahydrobiopterin; OCT = optimal cutting temperature; AGMAT = agmatinase.