Genes involved in conceptus–endometrial interactions in ruminants: insights from reductionism and thoughts on holistic approaches

Abstract

This review summarizes new knowledge on expression of genes and provides insights into approaches for study of conceptus-endometrial interactions in ruminants with emphasis on the peri-implantation stage of pregnancy. Conceptus-endometrial interactions in ruminants are complex and involve carefully orchestrated temporal and spatial alterations in gene expression regulated by hormones from the ovary and conceptus. Progesterone is the hormone of pregnancy and acts on the uterus to stimulate blastocyst survival, growth, and development. Inadequate progesterone levels or a delayed rise in progesterone is associated with pregnancy loss. The mononuclear trophectoderm cells of the elongating blastocyst synthesize and secrete interferon-t (IFNT), the pregnancy recognition signal. Trophoblast giant binucleate cells begin to differentiate and produce hormones including chorionic somatomammotropin 1 (CSH1 or placental lactogen). A number of genes, induced or stimulated by progesterone, IFNT, and/or CSH1 in a cell-specific manner, are implicated in trophectoderm adhesion to the endometrial luminal epithelium and regulation of conceptus growth and differentiation. Transcriptional profiling experiments are beginning to unravel the complex dynamics of conceptus-endometrial interactions in cattle and sheep. Future experiments should incorporate physiological models of pregnancy loss and be complemented by metabolomic studies of uterine lumen contents to more completely define factors required for blastocyst survival, growth, and implantation. Both reduction and holistic approaches will be important to understand the multifactorial phenomenon of recurrent pregnancy loss and provide a basis for new strategies to improve pregnancy outcome and reproductive efficiency in cattle and other domestic animals.

Evaluation of the uterine environment early in pregnancy establishment to characterise cows with a potentially superior ability to support conceptus survival

“…A gradation of IFNT was present with less in non-gravid horns of IR pregnancies with large conceptuses compared with gravid horns and less again in gravid horns of pregnancies with small conceptuses followed by very little in their non-gravid horns. This has several implications, as IFNT stimulates a plethora of pregnancy-related endometrial genes (see review, Spencer et al 2008) including ISG15 (Austin et al 1996), whose protein levels were greater in the gravid compared with non-gravid horns in the present study. Increased stimulation of the uterus would, in theory, provide a more favourable environment for the growth of the conceptus and, as a consequence, an increase in the numbers of binucleate cells available to secrete pregnancy-enhancing proteins such as CSH1 (Wooding 1992) and PAG9 (Green et al 2000).…”

“…Variation in proteins contained in the histotroph, which can lead to detrimental effects on conceptus growth (Gray et al 2002), may be specific to individual animals. Progesterone is one of the main regulators of the genes expressed in the endometrium that are involved in the preparation of the uterus during early pregnancy (Bazer et al 1979;Robinson et al 2008;Spencer et al 2008). This progesterone influence in early pregnancy affects conceptus growth and elongation with an association between lower progesterone concentrations during the early luteal phase and conceptuses with retarded development reported McNeill et al 2006).…”

Comparative aspects of implantation

“…Notably, SPP1 expression by uterine GE increased 12-fold during the receptive phase in women and up to 60-fold during pregnancy in rats suggesting a direct role in embryo-uterine interactions (see Kao et al 2002). Similar microarray studies are addressing uterine gene expression in cattle during early pregnancy (see Spencer et al 2008).…”

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

“…Synchronization of the complex events at the time of implantation relies on the timed release of molecular signals from the conceptus and the endometrium. Embryo-derived IFN-τ (IFNT) is the major signal of pregnancy in cattle, preventing luteolysis and regulating the expression of genes that are responsible for promoting local changes in the endometrium to accommodate the conceptus (1)(2)(3). In females, progesterone is the major driver of endometrial changes that prepare the uterus for conceptus implantation (4,5).…”