Progesterone-Regulated Changes in Endometrial Gene Expression Contribute to Advanced Conceptus Development in Cattle1

Abstract

The postovulatory rise in circulating progesterone (P4) concentrations is associated with increased pregnancy success in beef and dairy cattle. Our study objective was to determine how elevated P4 alters endometrial gene expression to advance conceptus development. Synchronized heifers were inseminated (Day 0) and randomly assigned to pregnant high P4 or to pregnant normal P4. All high P4 groups received a P4-release intravaginal device on Day 3 after insemination that increased P4 concentrations up to Day 7 (P < 0.05). Tissue was collected on Day 5, 7, 13, or 16 of pregnancy, and endometrial gene expression was analyzed using the bovine Affymetrix (Santa Clara, CA) microarrays. Microarray analyses demonstrated that the largest number of P4-regulated genes coincided with the day when the P4 profiles were different for the longest period. Genes with the largest fold change increase (such as DGAT2 and MSTN [also known as GDF8]) were associated with triglyceride synthesis and glucose transport, which can be utilized as an energy source for the developing embryo. Temporal changes occurred at different stages of early pregnancy, with the greatest difference occurring between well-separated stages of conceptus development. Validation of a number of genes by quantitative real-time PCR indicated that P4 supplementation advances endometrial gene expression by altering the time (FABP, DGAT2, and MSTN) or duration (CRYGS) of expression pattern for genes that contribute to the composition of histotroph.

Physiological and practical effects of progesterone on reproduction in dairy cattle

“…Recent studies continue to characterize the uterine effects of P4, inducing a uterine environment compatible with embryo growth, implantation, and maintenance of pregnancy (Arck et al, 2007;Forde et al, 2009;Bazer et al, 2012;Mullen et al, 2012a and.…”

“…However, it seems clear that there are dramatic differences in endometrial gene expression as the luteal phase progresses and that early supplementation with P4 can induce earlier expression of this P4 program (McNeill et al, 2006;Forde et al, 2009 and. The P4-induced changes in uterine gene expression can have dramatic consequences for the development of the embryos (Forde et al, 2011).…”

Maternal-embryo interaction leading up to the initiation of implantation of pregnancy in cattle

“…A variety of studies in cattle, including studies from our own group (Forde et al, 2009 and, evaluated genes expressed in the endometrium of the uterus during selected stages of the oestrous cycle and pregnancy (Bauersachs et al, 2005(Bauersachs et al, , 2006Mitko et al, 2008;MansouriAttia et al, 2009). However, data on gene expression during the post-hatching embryonic stages in cattle are sparse and, apart from a few exceptions, typically deal with candidate genes rather than being global in nature (Ushizawa et al, 2004;Hue et al, 2007;Degrelle et al, 2011).…”

“…Addition of P4 to culture medium had no effect on blastocyst formation (Clemente et al, 2009;Larson et al, 2011) or elongation after transfer to synchronized recipients (Clemente et al, 2009). Most convincingly, the embryo does not need to be present in the uterus during the period of P4 elevation in order to benefit from it (Clemente et al, 2009;O'Hara et al, 2014), strongly suggesting that the effect of P4 is via advancing the endometrial transcriptome (Forde et al, 2009) resulting in advancing conceptus elongation (Carter et al, 2008;Clemente et al, 2009). In addition reducing the output of P4 from the CL results in a delay in the temporal changes in the endometrial transcriptome resulting in delayed conceptus elongation in vivo (Forde et al, 2011a and2012a).…”

“…These are necessary to drive the changes required in the endometrium (and resulting histotroph), in order to provide the embryo/conceptus with the nutritional requirements it needs, which change as the embryo undergoes distinct morphological events. Data on the pre-hatching embryo indicate that the expression of a large number of genes and pathways (Forde et al, 2009(Forde et al, , 2011b(Forde et al, and 2012a, including aminopeptidase, lipoprotein lipase and lactotransferrin amino acids, ions and glucose (Hugentobler et al, 2007 and as well as proteins in the histotroph including Ezrin, triosephosphate isomerase, Glutathione S transferase mu, Cathepsin D, Annexin A1, which were more abundant in the histotroph than in circulation (Faulkner et al, 2012). This expression pattern is governed, in part, by the expression of the nuclear P4 receptor (PGR) in the LE and glandular epithelium (GE).…”