MicroRNA Signaling in Embryo Development

Abstract

Expression of microRNAs (miRNAs) is essential for embryonic development and serves important roles in gametogenesis. miRNAs are secreted into the extracellular environment by the embryo during the preimplantation stage of development. Several cell types secrete miRNAs into biological fluids in the extracellular environment. These fluid-derived miRNAs have been shown to circulate the body. Stable transport is dependent on proper packaging of the miRNAs into extracellular vesicles (EVs), including exosomes. These vesicles, which also contain RNA, DNA and proteins, are on the forefront of research on cell-to-cell communication. Interestingly, EVs have been identified in many reproductive fluids, such as uterine fluid, where their miRNA content is proposed to serve as a mechanism of crosstalk between the mother and conceptus. Here, we review the role of miRNAs in molecular signaling and discuss their transport during early embryo development and implantation.

Keywords: embryo; exosome; extracellular vesicle; implantation; miRNA; oocyte; signaling; sperm.

Figure 1

Basic pathway for miRNA biogenesis. Pri-miRNA is transcribed from a miRNA gene by RNA polymerase II (Pol II). DROSHA and DiGeorge syndrome critical region gene 8 (DGCR8) then bind together to form a microprocessor complex, which cleaves pri-miRNA to pre-miRNA. Pre-miRNA is exported from the nucleus to the cytoplasm by exportin-5 (EXP-5), where DICER converts pre-miRNA to mature miRNA along with TAR RNA-binding protein (TRBP) or PACT (also known as PRKRA) and Argonaute protein (AGO). DICER, TRBP or PACT, and AGO mediate duplex separation and loading of the mature miRNA into the RISC complex (RNA-induced silencing complex), whereby the miRNA can regulate gene expression.

Figure 2

Links of miRNA to gametogenesis, fertilization, and embryogenesis. Knockout models have been developed to assess necessity of miRNAs in oogenesis and spermatogenesis. DGCR8 and DROSHA are both representative of protein knockouts specific to the microprocessor complex which cleaves pri-miRNA to pre-miRNA. Interestingly, females are fertile when this complex is disrupted, but males are infertile. Importantly, these models do not represent environmental impact which can occur to alter miRNA profiles. At fertilization, both the sperm and the oocyte contribute miRNA. However, the oocyte’s miRNA is rapidly degraded, so its use remains undetermined. Alternatively, it has been shown that a sperm RNA, miR-34c, is required for the first cleavage division following fertilization. In remaining divisions, control over miRNA availability is dynamic in the embryo.

Figure 3

Schematic representation of miRNA crosstalk between a conceptus and mother. miRNAs have the potential to be transferred between maternal cells (represented as endometrium) and conceptus through various types of vehicles. These vehicles can be proteins (Argonaute 2 (AGO2) and Nucleophosmin 1 (NPM1)), extracellular vesicles, apoptotic blebs, high-density lipoproteins, and low-density lipoproteins. Upon delivery to either the mother or conceptus, the miRNA becomes bound to a RNA-induced silencing complex (RISC) and pairs to a complementary target mRNA. The target mRNA is then degraded, downregulated, or upregulated. This crosstalk can occur through direct cell–cell contact or miRNAs can be circulated and transferred in fluids, such as uterine fluid.

Figure 4

Summary of references on current knowledge of miRNAs in embryo development and signaling. A general schematic of references found throughout this article which outlines the links between miRNAs, embryo development, and signaling. Terms: extracellular vesicles (EVs), high-density lipoprotein (HDL), low-density lipoprotein (LDL), Argonaute (AGO) and nucleophosmin 1 (NPM1), microRNA(miRNA).