Temporal and Spatial Regulation of Let-7a in the Uterus During Embryo Implantation in the Rat

Abstract

Abstract. Mammalian embryonic implantation requires reciprocal interactions between implantation-competent blastocysts and a receptive uterus. Some microRNAs might play a key role during embryo implantation in the mouse, but the let-7a expression profiles in the rat uterus during peri-implantation are unknown. In the study, the expression of let-7a in the uterus during early pregnancy, pseudopregnancy, artificial decidualization and activation of delayed implantation was detected by Northern blotting and in situ hybridization. The effect of steroid hormones on let-7a expression was also detected by Northern blotting and in situ hybridization. Here, we found that the expression level of let-7a was higher on gestation day 6-7 (g.d. 6-7) in rats than on g.d. 4-5 and g.d.8-9. Let-7a was specifically localized in glandular and luminal epithelia and decidua. The expression of let-7a was not significantly different in the pseudopregnant uterus and increased significantly in the uteri of rats subjected to artificial decidualization and activation of delayed implantation. Treatment with estradiol-17β or progesterone significantly increased let-7a expression. Thus, let-7a expression was significantly induced by the process of embryo invasion, and this increased expression level was mainly induced by active blastocysts and decidualization during the window of implantation, implying that let-7a may participate in endometrial decidualization. Steroid hormones, estradiol-17β or progesterone stimulated let-7a expression. Key words: Embryo implantation, Hormone, Let-7a, Rat, Uterus (J. Reprod. Dev. 56: [73][74][75][76][77][78] 2010) ammalian implantation is a highly coordinated sequence of events that begins with the attachment of an embryo to the uterine luminal epithelium and ultimately results in formation of the placenta. The fertilized ova arrive in the rat uterus as blastocysts about 4.5 days after mating and uterine closure, embryo implantation can be initiated on day 5.5 and completed on day 7.75 [1,2]. Implantation of the embryo into the uterine wall is regulated by various factors including matrix metalloproteinases [3], hormones [4], cytokines [5] and integrins [6]. Although many molecules are now known to be involved in the process, the specific mechanisms associated with the onset of uterine receptivity remain to be determined.MicroRNAs (miRNAs) are small noncoding RNAs whose function as modulators of gene expression is crucial for proper control of cell growth and are known to participate in mouse embryo implantation [7,8]. The let-7 family is expressed differentially in the mouse uterus during the peri-implantation period [7,8]. Let-7a was initially found to regulate developmental timing in Caenorhabditis elegans [9]. Our previous study showed that let-7a is expressed differentially during follicular development in the mouse [10]. In humans, it plays an important role in the onset and development of forms of cancer [11,12]. Embryo implantation shares similar phenomena and mechanisms with tumor invasion [13].Th...

Steroid Hormone-regulated let-7b Mediates Cell Proliferation and Basigin Expression in the Mouse Endometrium

“…In all mammals, P4 is required for maternal support of conceptus survival and development, as well as for the establishment of endometrial receptivity for blastocyst implantation and maintenance of endocrine homeostasis by inhibiting the secretion of gonadotropin [10,11,30]. Studies have demonstrated that miRNAs in the endometrium could be regulated by steroid hormones [6,10,11,13,30]. The let-7 miRNA was originally identified in C. elegans as a regulator of developmental timing and cell proliferation [31].…”

“…Previous studies have indicated that Bsg is capable of inducing the expression of a range of MMPs, including MMP-1, MMP-2, MMP-3, . It was found that Bsg was expressed highly in the luminal and glandular epithelial cells in rat and mouse endometria on day 1 of gestation and decreased gradually until day 5 [10,11]. However, Bsg was shown to be strongly expressed in the primary decidua on day 6, and the expression level was significantly higher in the implantation sites than in the interimplantation sites [16,17].…”

“…The expression profiles of miRNAs are up-or downregulated in accordance with the changes in gene expressions during different physiological conditions, including embryo implantation and disease states [5][6][7][8][9][10][11]. By miRNA array analysis, 13 differentially-expressed miRNAs have been identified in mouse granulosa cells after hCG administration [12], and two out of 13 were highly upregulated (miRNA 132 and miRNA 122).…”

MicroRNAs, immune cells and pregnancy

“…A recent study demonstrated temporal and spatial regulation of let-7a and miR-320 that were differentially expressed in the rat uterus with expression affected by decidualization during the window of embryo implantation. 72,73 Additionally, a subset of miRNAs (hsa-miR-222, 221, 181b, 27b, 29b, 507, 143, 101, 30d, 30c and 23a) participates in gene reprogramming during endometrial stromal cell (ESC) decidualization in vitro and hsa-miR-222 was found to play a key role in differentiation of ESCs by regulating their terminal withdrawal from the cell cycle. 74 In our laboratory, studies on spontaneous fetal loss in pigs have provided evidence of selective miRNA expression in endometrial lymphocytes (unpublished data).…”

“…49 Taken together, miRNA regulation of angiogenesis participates in both pathological and physiological angiogenesis, and offers a novel therapeutic avenue to explore. Let-7a and miR-320 72,73 Uterine miRNAs…”