Clustered microRNAs: The molecular mechanism supporting the maintenance of luteal function during early pregnancy

Abstract

MicroRNAs (miRNAs) are recognized as the important regulators of ovarian function. However, little is known about the hormonal regulation of miRNA expression and the role of the specific miRNA‐mRNA interactions in corpus luteum. Therefore, the present study was undertaken to determine: (a) the expression of miRNAs in the corpus luteum in early pregnancy vs regression; (b) the effect of conceptus and uterine signals in the expression of selected miRNAs; and (c) the role of specific miRNA‐mRNA interactions in the molecular changes and secretory function of the corpus luteum in the pig. The results showed that the majority of miRNAs differentially expressed in the corpus luteum in early pregnancy vs regression belong to independent clusters (eg, miR‐99b, miR‐532), which are highly conserved among different animal species. The main conceptus signal in the pig (17β‐estradiol) elevated the luteal expression of the miR‐99b cluster and lowered the expression of NR4A1 and AKR1C1, the genes involved in corpus luteum regression. Furthermore, the delivery of miR‐99b cluster mimics to luteal tissue concomitantly decreased NR4A1 and AKR1C1 expression and enhanced progesterone secretion. The present study demonstrated that conceptus signals can support the maintenance of luteal function during pregnancy by clustered miRNA‐stimulated pathways, governing the expression of genes involved in luteal regression.

MiRNAs in the Peri-Implantation Period: Contribution to Embryo–Maternal Communication in Pigs

“…Therefore, we suggest that E2 increases the expression of miR-99b by the ESR1-SP1 pathway in the CL during early pregnancy. Remarkably, the aforementioned effects of E2 on the expression of the miRNA-99b cluster were concomitant with the inhibitory effect of E2 on the expression of NR4A1 and AKR1C1 in luteal tissue slices [40]. NR4A1 is encoded by immediate-early response genes, which can induce apoptosis or elevate transcription of AKR1C1, an enzyme responsible for the metabolism of progesterone [80,81].…”

“…Previously, the high expression of two clusters, miR-183-96-182 and miR-212-132, was noticed in the luteal vs. follicular tissue of cows, while miR-96 was found to be an important regulator of steroidogenesis and cell survival [74]. In pigs, miRNAs upregulated in the CL of pregnant animals belong to three independent clusters: miR-99b, miR-532, and miR-181a [40]. Again, among targets of miRNAs occurring in the same cluster (i.e., miR-532 and miR-99b), crucial regulators of luteolysis were found, including, for example, EDN1, FOS, JUN, NR4A1, OXTR, and PTGS2 [75,76,78].…”

“…Interestingly, a greater amount of miRNAs was found in the mature than in the developing CL, indicating their potential role in the maintenance of luteal function. Nevertheless, not many studies have provided information on the specific roles of selected miRNA-mRNA interactions on the function of luteal cells, while only a few have shown changes in the expression of miRNAs occurring in the CL during early pregnancy [40,72].…”

“…Recently, 14 differentially expressed miRNAs were identified in porcine CL collected right after maternal recognition of pregnancy (day 14 of pregnancy) and luteolysis (day 14 of the estrous cycle) [40]. Overall, seven miRNAs were upregulated (e.g., miR-21a-3p, miR-345-3p, miR-371-5p), and seven miRNAs were downregulated (e.g., miR-181a, miR-532-3p, miR-99b) in the porcine CL on day 14 of the estrous cycle compared to the corresponding day of pregnancy.…”

“…Luteotrophic and/or luteolytic factors were suggested to be effective modulators of miRNA expression [74,79]. In pigs, incubation of luteal tissue slices with E2 stimulated the expression of miRNAs belonging to the miR-99b cluster [40]. Further, bioinformatics analysis showed multiple SP1 and ESR1 binding sites in the promoter of the miR-99b cluster.…”