MicroRNAs: crucial regulators of placental development

in Reproduction
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  • Department of Biology, York University, Toronto, Ontario, Canada

MicroRNAs (miRNAs) are small non-coding single-stranded RNAs that are integral to a wide range of cellular processes mainly through the regulation of translation and mRNA stability of their target genes. The placenta is a transient organ that exists throughout gestation in mammals, facilitating nutrient and gas exchange and waste removal between the mother and the fetus. miRNAs are expressed in the placenta, and many studies have shown that miRNAs play an important role in regulating trophoblast differentiation, migration, invasion, proliferation, apoptosis, vasculogenesis/angiogenesis and cellular metabolism. In this review, we provide a brief overview of canonical and non-canonical pathways of miRNA biogenesis and mechanisms of miRNA actions. We highlight the current knowledge of the role of miRNAs in placental development. Finally, we point out several limitations of the current research and suggest future directions.

Abstract

MicroRNAs (miRNAs) are small non-coding single-stranded RNAs that are integral to a wide range of cellular processes mainly through the regulation of translation and mRNA stability of their target genes. The placenta is a transient organ that exists throughout gestation in mammals, facilitating nutrient and gas exchange and waste removal between the mother and the fetus. miRNAs are expressed in the placenta, and many studies have shown that miRNAs play an important role in regulating trophoblast differentiation, migration, invasion, proliferation, apoptosis, vasculogenesis/angiogenesis and cellular metabolism. In this review, we provide a brief overview of canonical and non-canonical pathways of miRNA biogenesis and mechanisms of miRNA actions. We highlight the current knowledge of the role of miRNAs in placental development. Finally, we point out several limitations of the current research and suggest future directions.

Introduction

MicroRNAs (miRNAs) have been established as major regulators of gene expression and are involved in many biological processes (Vasudevan 2012, Jonas & Izaurralde 2015). Since their discovery in 1993, miRNAs have been of great interest to researchers and many new advances have been made in understanding their structure, regulation and mechanisms of action (Lee et al. 1993, Jonas & Izaurralde 2015). Most studies have shown that miRNAs suppress gene expression when bound to the 3′ untranslated region (UTR) of target mRNAs by inhibiting translation and reducing mRNA stability (Behm-Ansmant et al. 2006, Chen et al. 2010, Miao et al. 2016). However, additional modes of action for miRNAs, such as transcriptional regulation and activation of gene expression, have also been reported (Benhamed et al. 2012, Vasudevan 2012, Catalanotto et al. 2016, Miao et al. 2016).

The placenta is a transient organ essential for the survival and development of mammalian embryos (Rossant & Cross 2001). This organ plays critical roles in mediating the exchange of respiratory gases, nutrients and waste products between the mother and the fetus (Rossant & Cross 2001, Regnault et al. 2002, Wooding & Burton 2008). In addition, the placenta also acts as an endocrine organ and produces many pregnancy-associated hormones and growth factors that help in sustaining pregnancy, preventing fetus rejection by the mother’s immune system and regulating fetal growth (Rossant & Cross 2001, Fu et al. 2013a, Ji et al. 2013).

Placental development is a spatially and temporally regulated process. This allows for increasing oxygen and nutrient demands required by the growing fetus to be met throughout gestation (Wooding & Burton 2008). Improper placental formation gives rise to many pregnancy-associated conditions such as preeclampsia and intrauterine growth restriction (Genbacev et al. 1996, Rossant & Cross 2001, Fu et al. 2013a). In recent years, the role of miRNAs in placentation has been increasingly recognized. In this review, we aim to provide an updated summary of the role of miRNAs in regulating various trophoblast activities and placental development. Dysregulation of miRNAs and their potential involvement in pregnancy complications has been discussed recently (Fu et al. 2013a, Mouillet et al. 2015, Escudero et al. 2016, Cai et al. 2017) and therefore will not be included in this review.

Overview of microRNAs

miRNAs are endogenous, small non-coding single-stranded RNAs, on average 22 nt in length, and are involved in multiple modes of gene regulation (Truesdell et al. 2012, Vasudevan 2012, Havens et al. 2014, Valinezhad Orang et al. 2014, Jonas & Izaurralde 2015, Catalanotto et al. 2016, Xiao et al. 2016). miRNAs are processed post- or co-transcriptionally from RNA polymerase II/III transcripts (Ha & Kim 2014). Approximately half of all known miRNA genes are intragenic, contained mostly within the introns and relatively few exons of protein coding genes (de Rie et al. 2017). The remaining miRNA genes are transcribed independent of a host gene via their own promoters (Kim & Kim 2007, Fuziwara & Kimura 2015).

The vast majority of miRNAs are processed through the canonical biogenesis pathway (Kim et al. 2016) (Fig. 1). Canonical miRNA biogenesis begins with the detection of the primary miRNA transcript (pri-miRNA), contained within nascent RNA, by DiGeorge Critical Region 8 (DGCR8) and associated proteins through recognition of the RNA N6-methyladenylated GGAC motif (Alarcon et al. 2015). In complex with DGCR8 is the nuclear RNase III endonuclease Drosha which cleaves the pri-miRNA duplex proximal to the base of the characteristic hairpin structure of pri-miRNA. This produces the excised precursor (pre)-miRNA containing a 2 nucleotide 3′ overhang (Han et al. 2004). Together, Drosha and DGCR8 are termed the microprocessor complex (Denli et al. 2004).

Figure 1
Figure 1

Overview of canonical microRNA biogenesis and mechanism. Canonical miRNA biogenesis is both Drosha- and Dicer-dependent. Following transcription, the primary (pri-) miRNA is identified and cleaved by the endoribonuclease, Drosha, to produce the precursor (pre-) miRNA. Nuclear export of the pre-miRNA is facilitated by the Exportin 5/RanGTP transport system. Once in the cytoplasm, the pre-miRNA is subject to terminal loop cleavage by the endoribonuclease Dicer. After cleavage, the mature miRNA duplex is loaded into the Argonaute family of proteins and the passenger strand is degraded, forming the miRNA-induced silencing complex (miRISC). The gene regulatory power of cytoplasmic miRISC typically culminates in gene silencing by mediating induction of translation inhibition, mRNA poly(A) deadenylation and mRNA degradation via interaction at the 3′ untranslated region of target mRNA. After target association and following recruitment of GW182 and associated proteins into miRISC, translation initiation is inhibited, preventing nascent protein translation of the target mRNA molecule. It is hypothesized that miRISC-induced dissociation of the translation initiation complex, eIF4F, from the 5′ cap of mRNA and/or its functional disruption suppresses translation initiation. Interaction of GW182 with poly(A) binding proteins (PABPC) and poly(A) deadenylase complexes PAN2/3 and CCR4-NOT localizes the 3′ mRNA tail to the miRISC complex, promoting efficient target mRNA deadenylation. Complete poly(A) deadenylation leads to decapping-protein 2 (DCP2)-mediated mRNA decapping, exposing the mRNA to 5′–3′ degradation via the exoribonuclease XRN1.

Citation: Reproduction 155, 6; 10.1530/REP-17-0603

Following pri-miRNA cleavage, the pre-miRNA is exported to the cytoplasm through an exportin 5 (XPO5)/RanGTP complex and then processed by the predominantly cytoplasmic RNase III endonuclease Dicer (Denli et al. 2004, Doyle et al. 2013). This cleavage, which removes the terminal loop, produces the mature miRNA duplex from pre-miRNA (Zhang et al. 2004). The labeling of the two strands of the miRNA duplex is based on the directionality of the strand in the pre-miRNA. The 5′ end of the pre-miRNA hairpin contains the 5p strand and the 3′ end the 3p strand (previously miRNA and miRNA*). Either the 5p or 3p strand of the miRNA duplex can be loaded into the Argonaute (AGO) family of proteins (AGO1–4 in humans) in an ATP-dependent manner (Yoda et al. 2010, Ha & Kim 2014); the strand that is loaded into AGO is termed the guide strand.

Several non-canonical miRNA biogenesis pathways have been elucidated (Ruby et al. 2007, Babiarz et al. 2008, Yang & Lai 2011, Abdelfattah et al. 2014, Ha & Kim 2014) and grouped into two general categories: Drosha/DGCR8-independent and Dicer-independent. These non-canonical pathways take advantage of the cellular machinery already in place to produce canonical miRNA by producing Drosha, Dicer and Argonaute substrates from discrete RNA sources such as small hairpin RNAs (shRNA), small nucleolar RNAs and splicing products (Yang & Lai 2011, Castellano & Stebbing 2013, Abdelfattah et al. 2014). Drosha/DGCR8-independent pre-miRNAs share a common trait in which separate processing mechanisms produce products which resemble Dicer substrates. For example, mirtrons encompass the group of pre-miRNAs produced from introns during mRNA splicing. Additionally, 7-methylguanosine (m7G)-capped pre-miRNAs are transcribed such that the nascent RNA does not need Drosha cleavage and can be directly exported from the nucleus through exportin 1 (Xie et al. 2013). Moreover, the m7G cap is thought to be the cause of a strong 3p strand bias. Dicer-independent miRNAs are processed from endogenous shRNA transcripts by Drosha and may be unique in their requirement for AGO2 to complete their processing within the cytoplasm. This group of pre-miRNAs is too short to be processed by Dicer, leading to the 5′ loading of the entire pre-miRNA into AGO2 (Abdelfattah et al. 2014). Slicing of the 3p strand and 3′–5′ trimming creates a strong 5p strand bias. Although non-canonical miRNAs may elicit post-transcriptional silencing capabilities and undergo regulation independent of canonical miRNAs, the vast majority of miRNAs are processed through the canonical biogenesis pathway, requiring both Drosha and Dicer to complete their maturation (Kim et al. 2016). However, consistent with their canonical counterparts, these non-canonical miRNAs have been linked to various cellular programs such as proliferation, de/differentiation, immune response, neural development and cellular metabolism (Abdelfattah et al. 2014).

Once AGO proteins are loaded and the miRNA duplex unwound, they form the minimal miRNA-induced silencing complex (miRISC) (Kawamata & Tomari 2010, Fabian & Sonenberg 2012). miRISC gains target specificity by recognition of miRNA response elements (MRE) on target RNA molecules, while the degree of complementarity determines, to some extent, the mode of regulation, i.e. direct or indirect gene silencing (Ameres et al. 2007, Jonas & Izaurralde 2015). A fully complementary miRNA:MRE promotes AGO2 endonuclease activity and cleavage of the target RNA molecule (Ameres et al. 2007). In turn, this also has the consequence of decreased miRNA stability as exact matches promote not only target cleavage but also degradation of the guide miRNA, although the mechanism is not well understood (Ameres & Zamore 2013). What is known is that the guide miRNA must first undergo the 3′ addition of adenosine or uracil which promotes 3′–5′ exonuclease activity, resulting in guide miRNA degradation (Krutzfeldt et al. 2005, Ameres et al. 2010).

In humans, the frequency of exact matches on target mRNA is rare (Jonas & Izaurralde 2015). The majority of validated MREs contain at least central mismatches to their guide miRNA, preventing AGO2 nuclease activity. As a consequence, AGO2 shifts from RNAi effector to mediator, and along with the non-endonucleolytic AGO family members act to recruit other proteins associated with mRNA stability. This has led to the detection of the miRNA seed region (nucleotides 2–8) that are crucial for many but not all miRNA:MRE interactions (Ellwanger et al. 2011, Xu et al. 2014, Miao et al. 2016). In most cases, miRNAs interact with the 3′ UTR of target mRNAs, resulting in translation inhibition and mRNA deadenylation and decapping (Huntzinger & Izaurralde 2011, Fabian & Sonenberg 2012, Meijer et al. 2013, Ipsaro & Joshua-Tor 2015).

To form an miRISC complex capable of post-transcriptional gene silencing, mRNA-bound miRISC recruits the GW182 family of proteins which acts as a scaffold to further recruit effector protein complexes (Behm-Ansmant et al. 2006). Both the PAN2–PAN3 and CCR4–NOT deadenylase complexes are recruited through the unstructured, tryptophan (W) repeats of GW182 (Christie et al. 2013, Jonas & Izaurralde 2015). PAN2–PAN3 initially catalyzes target mRNA poly(A) deadenylation which is promoted through the interaction of W-repeats to poly(A)-binding proteins (PABPC), bringing both the mRNA poly(A) tail and deadenylase into close proximity (Jonas & Izaurralde 2015). The CCR4–NOT complex completes the deadenylation process and is followed by mRNA decapping facilitated by decapping protein 2 (DCP2) and associated proteins (Behm-Ansmant et al. 2006). Decapped and deadenylated mRNA are then degraded from the 5′ end by the 5′–3′ exoribonuclease 1 (XRN1) (Braun et al. 2012) (Fig. 1).

While most miRNA studies focus on how miRNAs target mRNAs by binding to MREs at the 3′ UTR to suppress their expression, MREs have also been reported in the 5′ UTR. miRISC interactions within the 5′ UTR have been shown to both promote and suppress translation through mRNA-specific mechanisms, discussed in detail in Vasudevan (2012) and Valinezhad Orang et al. (2014). Moreover, cell-state-specific miRNA-mediated translational activation has been observed in human quiescent cells where nuclear AGO2 complexes with Fragile-x-mental-retardation-related protein 1 (FXR1) instead of GW182 (Truesdell et al. 2012). This complex was found to interact with nuclear mRNA targets which in turn led to translational activation following export to the cytoplasm (Truesdell et al. 2012).

Overview of placental development

Soon after fertilization, asymmetric cell division of the blastomere gives rise to different cell populations, an outer cell layer surrounding an inner cell population (Johnson & Ziomek 1981, Viswanathan et al. 2009). The blastocyst is formed when the outer cell layer differentiates into a layer of trophoblasts termed the trophectoderm (TE) and the inner cell population differentiates into the inner cell mass (ICM). The TE will later give rise to the placenta, while the ICM will develop into the embryo and the visceral endoderm (yolk sac) (Viswanathan et al. 2009, Maltepe & Fisher 2015).

With the trophectoderm formed, the blastocyst is ready for implantation (Caniggia et al. 2000). Implantation starts with the adhesion of the TE onto the receptive decidualized endometrium through a complex network of cell–cell communication events (Red-Horse et al. 2004). This leads to the invasion of the blastocyst through the extracellular matrix of the decidua by the proliferating and differentiating trophectoderm layer, embedding it deep into the uterine wall (Red-Horse et al. 2004, Noris et al. 2005, Wooding & Burton 2008).

Once the blastocyst is embedded within the uterine wall, the process of placenta formation, termed placentation, begins with the differentiation of the TE cells into the different trophoblast lineages (Red-Horse et al. 2004, Maltepe & Fisher 2015). Placentation in eutherian mammals is more complex compared to marsupial mammals (Moffett & Loke 2006, Carter 2007, Maltepe & Fisher 2015). Moreover, among eutherian mammals, placentation varies considerably in the degree of trophoblast invasiveness from minimal invasion occurring in epitheliochorial placentation (e.g. pigs and sheep), intermediate invasion in endotheliochorial placentation (e.g. dogs and cats) and maximal invasion in hemochorial placentation (e.g. humans and rodents) (Moffett & Loke 2006, Carter 2007, Wooding & Burton 2008).

In humans, placentation consists, in part, of the differentiation and proliferation of the TE to form a branching network of villi that are in direct contact with the maternal circulation while simultaneously maintaining a barrier between the fetal and maternal blood (Kaufmann et al. 2004, Wooding & Burton 2008, Schmidt et al. 2015). The villi are the functional units of the placenta. They facilitate and respond to the demands of the developing fetus by regulating the exchange of gases, nutrients and wastes through the villus core, which consists of the mesenchyme and fetal blood vessels (Kaufmann et al. 2004). The tips of the branching villous network that come into direct contact with the endometrium are termed the anchoring villi, while the remaining villi, which float freely in the blood-filled intervillous space, are called the floating villi (Maltepe et al. 2010).

The highly proliferative, undifferentiated cytotrophoblast (CTB) progenitor cells of the placental villi differentiate into two general pathways. CTBs can either fuse to form a multinucleated monolayer of syncytiotrophoblasts (STBs) that enclose the villous stroma, or differentiate into invasive extravillous trophoblasts (EVTs) that infiltrate the endometrium and a portion of the myometrium (Cartwright et al. 2010). STBs function as a barrier, or more precisely, as an interface between fetal and maternal blood as well as in the production of pregnancy-associated hormones and growth factors important for placental and fetal development and growth (Fu et al. 2013a). The mechanisms that facilitate CTB fusion and production of the STB layer are still under investigation; however, formation of gap junctions, activation of apoptotic pathways and the expression of endogenous retroviral proteins such as syncytin appear to be key mechanisms (Wooding & Burton 2008).

In the EVT pathway, the proliferating CTBs of the anchoring villi form a column that attaches to the uterine epithelium and subsequently differentiates into interstitial EVTs (Anin et al. 2004, Ji et al. 2013). Interstitial EVTs (iEVTs) invade the decidua and one-third of the myometrium where they further differentiate into the multinucleated placental bed giant cells (Fu et al. 2013a). Endovascular EVTs (enEVTs) acquire endothelial-like characteristics and invade the maternal spiral arteries to replace the endothelial cells. This results in the transformation of spiral arteries into distended, thin-walled vessels to ensure continuous maternal blood flow to the placenta and to maintain sufficient oxygen and nutrient supplies for the growing embryo (Anin et al. 2004, Lyall et al. 2013). Recently, endoglandular EVTs (egEVT) have been identified as a potential third subtype of EVTs (Moser et al. 2010, 2015). Initial findings suggest that egEVT disintegrate uterine glands and open the gland lumen to the intervillous space releasing glandular secretions that may impact placentation (Burton et al. 2007, Moser et al. 2015).

Many studies on human placental development, including the miRNAs work discussed in the following sections, have been carried out using in vitro models, such as immortalized trophoblast and choriocarcinoma cell lines, primary cultures of trophoblasts and/or villous explants from first trimester placenta. Rodents, especially mice, have also been used as a model. It is important to recognize that each of these models have pros and cons. Although cell lines are easy to work with, especially with respect to transient and stable transfection of genes, there are significant differences in gene expression signatures between cell lines and primary trophoblasts (Bilban et al. 2010). For example, chromosome 19 miRNA cluster (C19MC) members are not expressed in HTR8/SVneo cells, while chromosome 14 miRNA cluster (C14MC) members cannot be detected in JEG-3 cells (Mouillet et al. 2011, Morales-Prieto et al. 2014). Primary CTBs have been used mainly to study the differentiation of CTB to STB, but these cells have a limited life span and can only be used to study the short-term effects of transiently transfected miRNAs. Villous explants maintain the cellular architecture and mimic more closely the in vivo environment (Miller et al. 2005). However, only the short-term effect of miRNA overexpression or inhibition can be examined. The mouse model provides some insights into the in vivo functions of miRNAs, but it should be noted that there are significant differences between the mouse and human placentation that can affect the transferability of findings to humans (Wildman et al. 2006, Carter 2007, Maltepe & Fisher 2015, Schmidt et al. 2015, Grigsby 2016). For example, trophoblast invasion during early mouse placentation is shallow as it only extends into the decidua, whereas in humans, it proceeds to the myometrium (Carter 2007, Maltepe & Fisher 2015, Schmidt et al. 2015). Also, mouse trophoblasts express major histocompatibility complex (MHC)-K, -D and -L, while human trophoblasts express human leukocyte antigen G (HLA-G) or HLA-C. This leads to different interaction dynamics between uterine immune cells and invading trophoblasts (Chaouat & Clark 2015, Schmidt et al. 2015). Importantly, there are different miRNA expression profiles between human and mouse placentas. Specifically, C19MC is expressed only in primates with no orthologs found in rodents (Morales-Prieto et al. 2014), while miRNAs of the Sfmbt2 cluster are rodent-specific (Zheng et al. 2011, Schmidt et al. 2015, Inoue et al. 2017). Also, C14MC in humans shows a divergence in rodents where it is located on chromosome 12 and lacks multiple members found in humans (Seitz et al. 2004). Therefore, in the following discussion, we will point out which model(s) was used in each study.

miRNAs in trophectoderm development and implantation

Many studies carried out in mice suggest that miRNAs play a role in trophectoderm development. Examination of mouse miRNA expression patterns during trophectoderm specification has revealed let-7, miR-21, miR-29c, miR-96, miR-125a, miR-214, miR-297, miR-376a and miR-424 as candidates that may play a role in this process (Viswanathan et al. 2009, Nosi et al. 2017). In mouse embryonic stem cells (ESC), overexpression of miR-15b, miR-322 and miR-467 suppressed their embryonic fate and led to the induction of a trophoblast stem-cell (TSC)-like phenotype. Further analysis revealed that these miRNAs target transcription factors Sall1, Sall4, Pou5f1 and Nanog (Nosi et al. 2017), that are important for the maintenance of ESC self-renewal and pluripotency. In addition, the miR-302/367 cluster was found to promote TE differentiation in humans by targeting bone morphogenetic protein (BMP) inhibitors TOB2, DAZAP2 and SLAIN1 (Lipchina et al. 2011); BMP4 is a member of the transforming growth factor beta (TGFB) superfamily and is involved in promoting TE differentiation (Xu et al. 2002, Wu et al. 2008). In a human pulmonary artery cell line, miR-302 was also shown to target BMP4 receptor 2, while BMP signaling led to the transcriptional downregulation of the miRNA-302/367 gene cluster (Kang et al. 2012), which if it also occurs in trophoblasts could create an interesting signal-buffering dynamic.

Limited evidence obtained so far has suggested that miRNAs play a role in regulating implantation. First, studies in mice have shown that miRNAs are differentially expressed between implantation sites and inter-implantation sites in the endometrium (Chakrabarty et al. 2007, Hu et al. 2008, Geng et al. 2014). Further studies revealed that overexpression of miR-145 impaired the attachment of mouse embryos to endometrial epithelial cells by targeting insulin-like growth factor 1 receptor (Igf1r) (Kang et al. 2015). Finally, Dicer knockdown in mouse blastocysts altered miRNAs expression and resulted in a lower implantation rate (Cheong et al. 2014). In humans, a number of miRNAs in the endometrium, including miR-145, were also found to be differentially expressed between women who repeatedly fail to have successful implantation and fertile women (Revel et al. 2011). These findings suggest a possible role of miRNAs in regulating implantation; however, more studies are required to understand the functions of miRNAs and their underlying mechanisms in this process.

Another important aspect of successful implantation is the interaction between the fetal blastocyst and the maternal immune cells. Early in pregnancy, maternal uterine natural killer (uNK) cells, T cells, B cells, macrophages and dendritic cells are recruited into the endometrium at the site of implantation to help regulate placental and fetal development (Szekeres-Bartho 2002, Bidarimath et al. 2014, Zhang et al. 2016a). As mentioned earlier, human EVT expresses a limited variety of MHC molecules, mostly HLA-G and HLA-C (Bidarimath et al. 2014, Schmidt et al. 2015, Hackmon et al. 2017). HLA-G interacts with the maternal killer immunoglobulin-like receptors expressed by uNK cells, resulting in the activation of uNK cytokine production but not its cytotoxicity response (Rajagopalan et al. 2006). This in turn promotes maternal immunological tolerance and placental development and vascularization (Bidarimath et al. 2014, Ratsep et al. 2015). Both miR-148a and miR-152 were found to bind the 3′ UTR of HLA-G, amplified from the JEG-3 human trophoblast cell line, downregulating its expression and thereby reducing HLA-G mediated inhibition of natural killer cells cytotoxicity (Manaster et al. 2012). These findings suggest that miRNAs play a role in regulating maternal immunological tolerance to invading EVT. In addition, miRNAs have also been shown to help regulate other maternal immune cells such as macrophages, endometrial dendritic cells and T cells in the pregnant uterus and have been extensively reviewed in Robertson and Moldenhauer (2014), Mori et al. (2016), Schjenken et al. (2016) and Robertson et al. (2017).

Interestingly, miRNAs were also shown to promote antiviral immunity in both trophoblast and non-trophoblast cells. In alignment with the role of placenta to protect the developing fetus, trophoblasts are the first line of defense against external factors that can impair fetal development. Therefore, it is not surprising that primary human trophoblasts are highly resistant to viral infection (Delorme-Axford et al. 2013). More importantly, they can confer this resistance to other types of cells when these cells uptake exosomes naturally secreted by primary trophoblasts; the exosomes were found to contain members of C19MC, miR-512-3p, miR-516b-5p and miR-517-3p (Bayer et al. 2015). These C19MC miRNAs initiated autophagy in recipient cells without leading to cell death which was suggested to impair viral replicability (Delorme-Axford et al. 2013, Bayer et al. 2015). Thus, miRNAs play a dynamic role to not only promote decidual immune tolerance in support of the growing fetus but also protect both mother and fetus from viral infection (Mouillet et al. 2014, Ouyang et al. 2014).

miRNAs in trophoblast differentiation, migration and invasion

Several studies have suggested that miRNAs are important regulators of CTB to STB differentiation. Microarray analyses of miRNA expression profiles in primary trophoblast before and after their differentiation into STB have revealed that multiple members of C19MC such as miR-515-5p, miR-518f, miR-519c-3p and miR-519e-5p were significantly downregulated during CTB to STB differentiation (Zhang et al. 2016b). Further investigation showed that miR-515-5p targeted several genes that play critical roles in STB differentiation, including human glial cell missing-1 (GCM1) (Yu et al. 2002, Liang et al. 2010, Wakeland et al. 2017) and frizzled 5 (FZD5) (Lu et al. 2013) and significantly reduced cell fusion (Zhang et al. 2016b). Another miRNA gene cluster is the miR-17–92 family that is located on chromosome 13 and encodes six miRNAs (miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a and miR-92a) (Concepcion et al. 2012). Multiple members of the miRNA-17–92 cluster, and its paralog cluster miR-106a–363, have been found to silence GCM1 in primary cultures of human trophoblasts. These miRNAs are downregulated during CTB to STB differentiation, thereby promoting the differentiation process (Kumar et al. 2013). Studies from our laboratory have demonstrated that miR-378a-5p suppressed BeWo cell fusion and STB marker gene expression by targeting cyclin G2 (CCNG2), suggesting that it inhibits STB differentiation (Nadeem et al. 2014).

Many studies have reported that miRNAs regulate EVT differentiation, migration and invasion by targeting key pathways known to regulate these processes. Early placentation occurs in a hypoxic environment, and oxygen tension has been reported to regulate many cellular processes in the placenta, including proliferation, EVT differentiation and invasion (Chang et al. 2018). However, the precise role of oxygen tension in EVT differentiation and invasion is still not well understood. Earlier studies have suggested that hypoxic conditions during early pregnancy are in part responsible for the high rate of trophoblast proliferation and inhibition of EVT invasion (Red-Horse et al. 2004). As the trophoblasts invade deeper into the uterus, where oxygen levels are higher, they shift from a more proliferative phenotype to a more migratory and invasive phenotype (Genbacev et al. 1997, Kaufmann & Castellucci 1997, Knofler 2010). However, hypoxia was recently found to promote EVT differentiation in a hypoxia-inducible factor (HIF)-dependent manner while inhibiting STB differentiation in primary cultures of human CTB (Wakeland et al. 2017). Thus, it is proposed that low oxygen induces the differentiation into immature EVT, but further maturation of EVT and invasion increase with rising oxygen tension (Chang et al. 2018).

Since hypoxia plays an important role in early placental development, studies have investigated its effects on miRNA expression and function (Donker et al. 2007, Mouillet et al. 2010, Fu et al. 2013a). They have revealed a group of miRNAs that are upregulated under hypoxia, a subset of which, hypoxamirs, and are under direct regulation of hypoxia-induced transcription factors (Kulshreshtha et al. 2007). MiR-210 is the most well-studied example of hypoxamirs, upregulated directly by HIF1A (Camps et al. 2008); additionally, it is regulated by a hypoxia-responsive transcription factor, nuclear factor kappa-B subunit p50 (NFKB1), in primary human trophoblasts (Zhang et al. 2012). It was reported that miR-210 inhibited migration and invasion in primary CTBs (Zhang et al. 2012), HTR8/SVneo cell line (Luo et al. 2016), and primary ETVs (Anton et al. 2013) by targeting ephrin-A3 (EFNA3), homeobox-A9 (HOXA9) (Zhang et al. 2012), and thrombospondin type I domain containing 7A (THSD7A) (Luo et al. 2016) or by activating the MAPK pathway (Anton et al. 2013). However, knockout of mir-210 did not result in significant changes in fetal or placental weight and non-severe hypoxia (12% O2) did not increase miR-210 in these mice, suggesting that miR-210 may be dispensable for fetal-placental development under normoxic and non-severe hypoxic conditions (Krawczynski et al. 2016). Thus, the role of miR-210 in hypoxia-regulated placental development requires further investigation.

miRNAs also regulate EVT differentiation and invasion by modulating growth factor signaling. An important family of growth factors in placental development is the TGFB superfamily. Many miRNAs have been found to enhance EVT migration and invasion by targeting members of the TGFB family. For example, miR-376c targeted both activin receptor-like kinase 7 (ALK7) and ALK5 to impede TGFB/Nodal signaling (Fu et al. 2013b), while miR-378a-5p targeted the ligand Nodal (Luo et al. 2012) to promote migration and invasion in HTR8/SVneo cells and EVT outgrowth in first trimester placental villous explants. Similarly, miR-195 enhanced trophoblast invasion by targeting activin receptor type-2B, a type II receptor for Nodal and activin, in HTR8/SVneo cells (Wu et al. 2016).

Using HTR8/SVneo, JEG-3 or BeWo trophoblast cell lines, several studies have suggested that miRNAs also regulate EVT motility by targeting other genes involved in regulating cell invasion. Both miR-346 and miR-582-3p targeted endocrine-gland-derived vascular endothelial growth factor (EG-VEGF) as well as matrix metalloproteinase 2 (MMP2) and MMP9, and strongly inhibited the migratory and invasive abilities of trophoblasts (Su et al. 2017). Similarly, miR-93 (Pan et al. 2017) and miR-204 (Yu et al. 2015), which targeted MMP2 and MMP9, respectively, inhibit cell invasion. Members of the C19MC, miR-519d-3p (Ding et al. 2015) and miR-520g (Jiang et al. 2017a) also targeted MMP2 and inhibited migration and invasion, while miR-520c-3p inhibited invasion by suppressing CD44, which is needed for the interaction between EVTs and decidual extracellular matrix (Takahashi et al. 2017). On the other hand, miR-21 promoted not only migration and invasion but also cell proliferation (Chaiwangyen et al. 2015). Among its targets is phosphatase and tensin homolog (PTEN), a known inhibitor of the AKT pathway. PTEN dephosphorylates phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), leading to inactivation of AKT which is involved in trophoblast cell motility (Chaiwangyen et al. 2015). MiR-34a inhibited invasion by targeting MYC (Sun et al. 2015). MiR-20a is another such miRNA where it inhibited not only trophoblast motility but also cell proliferation by targeting forkhead box protein A1 (FOXA1) (Wang et al. 2014). As all these studies were only done in cell lines, the significance of these miRNAs in EVT differentiation and invasion requires validation using additional model systems.

miRNAs in trophoblast proliferation and apoptosis

Proliferation and apoptosis are important mechanisms of proper placental development; disruption of the equilibrium between cell division and death impairs placental function (Levy et al. 2000). A recent in vivo study in mice has demonstrated the critical role of the miR-290 cluster in placental cell proliferation and placental growth; deletion of the miR-290 cluster resulted in the reduction of trophoblast progenitor cell proliferation and placental size (Paikari et al. 2017). In addition, many in vitro studies have shown that miRNAs regulate trophoblast proliferation and apoptosis. For example, miR-378a-5p (Luo et al. 2012) and miR-376c (Fu et al. 2013b) enhanced HTR8/SVneo cell proliferation and survival and EVT outgrowth in villous explants by inhibiting Nodal/TGFB signaling. On the other hand, miR-195 inhibited apoptosis through targeting of inducible nitric oxide synthase (iNOS) in HTR8/SVneo cells (Wang et al. 2017). Furthermore, overexpression of miR-377 and let-7a, which are upregulated in term placenta samples versus first trimester samples, decreased trophoblast proliferation by reducing ERK and/or MYC expression in first trimester placental explants (Farrokhnia et al. 2014). Together, these studies suggest a potential regulatory link between miRNAs and proliferation in human trophoblasts.

Studies using multiple human trophoblast cell lines suggested a role of miRNAs in the regulation of apoptosis. The miR-29 family (miR-29a/b/c) promoted apoptosis by targeting myeloid cell leukemia-1 (MCL1), an apoptosis regulator and a member of the BLC2 family (Li et al. 2013, Gu et al. 2016). Overexpression of miR-18a increased apoptosis by inducing the expression of estrogen receptor alpha (ESR1) (Zhu et al. 2015), while miR-128a induced apoptosis via the mitochondrial pathway by downregulating BAX (Ding et al. 2016) and miR-30a-3p by inhibiting IGF1 (Niu et al. 2018). On the other hand, miR-101 targeted endoplasmic reticulum protein 44 (ERP44) to suppress ER-stress-induced apoptosis (Zou et al. 2014). Again, as majority of these studies were carried out using only cell lines, more studies are required to confirm the involvement of these miRNAs in trophoblast cell proliferation and apoptosis.

miRNAs in placental vascular development

Placenta vascularization is essential to meet the metabolic demands of the rapidly growing fetus. Delayed or reduced vascular development of the placenta can result in compromised pregnancies (Reynolds & Redmer 2001). Placental vascular formation includes vasculogenesis, the de novo synthesis of vessels within the villi core and angiogenesis, the formation of new vessels from preexisting ones (Huppertz & Peeters 2005, Demir et al. 2007). Recently, deletion of the miR-290 cluster in mice has been reported to cause disorganization of the vasculature in the labyrinth (Paikari et al. 2017), providing strong evidence that miRNAs are important regulators of placenta vascular development.

Several miRNAs have also been suggested to play a role in vasculogenesis and angiogenesis. It was reported that miR-126 promotes proliferation, differentiation and migration of human endothelial progenitor cells by targeting an anti-angiogenic factor PIK3R2 (Yan et al. 2013). Also, in pregnant rats, miR-126 was found to increase vascular sprouting, as well as placental and fetal weights (Yan et al. 2013). The importance of miR-126 in placenta vascular development is further supported by the finding that downregulation of miR-126 contributes to endothelial dysfunction (Yan et al. 2013).

VEGF is a highly regulated pro-angiogenic factor known to initiate vasculogenesis in the placenta, induce endothelial cell proliferation and migration and inhibit apoptosis (Wang & Zhao 2010). Several miRNAs have been reported to target VEGF. For example, miR-16 directly targeted VEGF to inhibit HUVEC proliferation, migration and tube formation (Zhu et al. 2016). Also, overexpressing miR-16 in mice placentas decreased placental and fetal weights and inhibited the total placental vasculature and capillary number (Zhu et al. 2016). Similarly, miR-136 (Ji et al. 2017), miR-200c, -20a and -20b (Hu et al. 2016) also targeted VEGF, and may exert inhibitory effects on angiogenesis. However, whether these miRNAs affect placental vascular development has not been investigated. In CD34+ endothelial cells isolated from human umbilical cord blood, miR-210 was induced by VEGF and exerted proangiogenic effects (Alaiti et al. 2012), suggesting that miR-210 may play a role in placental angiogenesis.

miRNAs in trophoblast cellular metabolism

Early in pregnancy, and before spiral artery plug dissolution, placental and fetal nutrients and oxygen supply is dependent on endometrial secretions and maternal plasma (Murray 2012). As a consequence, first trimester placenta has a relatively low oxygen concentration (1–3%) (Pringle et al. 2010, Murray 2012) and placental cells use glycolysis and lactic acid fermentation for ATP synthesis as their primary metabolic fuel source to conserve oxygen supplies for fetal tissues (Murray 2012, Kolahi et al. 2017). Moreover, HIF1A downregulates mitochondrial oxygen consumption (Papandreou et al. 2006) to reduce ROS production at complex 3 of the electron transport chain (ETC) in the mitochondria (Colleoni et al. 2013). The hypoxia-induced miR-210 has been reported to regulate cellular metabolism. Using primary human trophoblasts, it was found that overexpression of miR-210 reduced, while inhibition of miR-210 increased, mitochondrial respiration (Muralimanoharan et al. 2012). Iron-sulfur complex assembly proteins (ISCU) and cytochrome-c oxidase assembly protein (COX10), which play important roles in the mitochondria ETC and tricarboxylic acid cycle, have been shown to be targeted by miR-210 in human endothelial and cancer cell lines (Chan et al. 2009, Chen et al. 2010). In trophoblasts, miR-210 was also found to directly target ISCU and to reduce the expression of ISCU and COX10 (Muralimanoharan et al. 2012, Colleoni et al. 2013), suggesting that these genes are involved in miR-210-regulated trophoblast mitochondrial adaptation to low oxygen.

In addition to miR-210, several other miRNAs are also involved in mitochondrial biogenesis and function. For example, miR-130b-3p was found to decrease signals for mitochondrial biogenesis and adaptation to oxidative stress through targeting of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A), a major regulator of mitochondrial biogenesis and energy metabolism (Jiang et al. 2017b). Also, miR-143 overexpression in primary human trophoblasts upregulated mitochondrial complexes 1, 2 and 3 but not 4 and 5 (Muralimanoharan et al. 2016), thus improving mitochondrial function. It also targeted hexokinase-2, a rate-limiting enzyme of glycolysis, and as a result reduced the glycolysis rate in trophoblasts (Muralimanoharan et al. 2016). Together, these miRNAs may help regulate trophoblast metabolic adaptation to change in oxygen levels throughout gestation.

Concluding remarks

The placenta is an essential organ for pregnancy. The proper development of placenta requires precise regulation by many signaling molecules, including miRNAs. Increasing evidence suggests that miRNAs play important roles in regulating many key processes in placental development, such as trophoblast differentiation, migration, invasion, proliferation, apoptosis, vasculogenesis/angiogenesis and cellular metabolism (Fig. 2). Although several recent in vivo studies in animal models have provided strong evidence that miRNAs are critical regulators of placental development (Ito et al. 2015, Zhu et al. 2016, Paikari et al. 2017), there are differences in placental development and placental miRNA expression profiles between mice and humans. Therefore, applications of findings from different animal models into humans should be treated with caution. Furthermore, most reported miRNA studies in placenta were performed using human cell lines derived from immortalized first trimester trophoblasts or choriocarcinoma, while only a smaller proportion of studies used primary cultures of trophoblasts, placental explants and/or clinical samples. There are also reports of differential miRNA expression patterns between primary cells and immortalized trophoblast cell lines. Therefore, the use of multiple model systems should be emphasized.

Figure 2
Figure 2

MicroRNAs involved in placental development. Proper development and functioning of the placenta requires precise control of trophoblast proliferation, apoptosis, differentiation, cellular metabolism, as well as vasculogenesis/angiogenesis. Many miRNAs have been suggested to play a regulatory role in one or more of these processes and are listed in this Venn diagram.

Citation: Reproduction 155, 6; 10.1530/REP-17-0603

Most studies conducted today focus on one or a few target genes. Since miRNAs target many genes, the use of multi-omics approaches to investigate gene networks responsible for the regulatory functions of miRNAs in the placenta will provide a better understanding of how miRNAs are involved in regulating placental development. Finally, all miRNA studies in placenta focused on canonical 3′ UTR-mediated gene silencing. As our understanding of the different miRNA biogenesis pathways and modes of miRNA action continues to expand, their novel contributions to modulating cellular activities during pregnancy should also be investigated.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

Work in our laboratory was supported by grants from the Canadian Institutes of Health Research (MOP-81370, CCI-92222, CCI-132565 and PJT-153146) to C P. H H and J O were supported by the Ontario Graduate Scholarship.

Acknowledgement

We would like to thank Dr Jelena Brkic for critical reading and editing of the manuscript.

References

  • Abdelfattah AM, Park C & Choi MY 2014 Update on non-canonical microRNAs. Biomolecular Concepts 5 275287. (https://doi.org/10.1515/bmc-2014-0012)

  • Alaiti MA, Ishikawa M, Masuda H, Simon DI, Jain MK, Asahara T & Costa MA 2012 Up-regulation of miR-210 by vascular endothelial growth factor in ex vivo expanded CD34+ cells enhances cell-mediated angiogenesis. Journal of Cellular and Molecular Medicine 16 24132421. (https://doi.org/10.1111/j.1582-4934.2012.01557.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alarcon CR, Lee H, Goodarzi H, Halberg N & Tavazoie SF 2015 N6-methyladenosine marks primary microRNAs for processing. Nature 519 482485. (https://doi.org/10.1038/nature14281)

  • Ameres SL & Zamore PD 2013 Diversifying microRNA sequence and function. Nature Reviews Molecular Cell Biology 14 475488. (https://doi.org/10.1038/nrm3611)

  • Ameres S, Martinez J & Schroeder R 2007 Molecular basis for target RNA recognition and cleavage by human RISC. Cell 130 101112. (https://doi.org/10.1016/j.cell.2007.04.037)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ameres SL, Horwich MD, Hung JH, Xu J, Ghildiyal M, Weng Z & Zamore PD 2010 Target RNA-directed trimming and tailing of small silencing RNAs. Science 328 15341539. (https://doi.org/10.1126/science.1187058)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anin SR, Vince G & Quenby S 2004 Trophoblast invasion. Human Fertility 7 169174. (https://doi.org/10.1080/14647270400006911)

  • Anton L, Olarerin-George AO, Schwartz N, Srinivas S, Bastek J, Hogenesch JB & Elovitz MA 2013 miR-210 inhibits trophoblast invasion and is a serum biomarker for preeclampsia. American Journal of Pathology 183 14371445. (https://doi.org/10.1016/j.ajpath.2013.07.021)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Babiarz JE, Ruby JG, Wang Y, Bartel DP & Blelloch R 2008 Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. Genes and Development 22 27732785. (https://doi.org/10.1101/gad.1705308)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bayer A, Delorme-Axford E, Sleigher C, Frey TK, Trobaugh DW, Klimstra WB, Emert-Sedlak LA, Smithgall TE, Kinchington PR & Vadia S 2015 Human trophoblasts confer resistance to viruses implicated in perinatal infection. American Journal of Obstetrics and Gynecology 212 71.e171.e8. (https://doi.org/10.1016/j.ajog.2014.07.060)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Behm-Ansmant I, Rehwinkel J, Doerks T, Stark A, Bork P & Izaurralde E 2006 MRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes and Development 20 18851898. (https://doi.org/10.1101/gad.1424106)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Benhamed M, Herbig U, Ye T, Dejean A & Bischof O 2012 Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells. Nature Cell Biology 14 266275. (https://doi.org/10.1038/ncb2443)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bidarimath M, Khalaj K, Wessels JM & Tayade C 2014 MicroRNAs, immune cells and pregnancy. Cellular and Molecular Immunology 11 538547. (https://doi.org/10.1038/cmi.2014.45)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bilban M, Tauber S, Haslinger P, Pollheimer J, Saleh L, Pehamberger H, Wagner O & Knofler M 2010 Trophoblast invasion: assessment of cellular models using gene expression signatures. Placenta 31 989996. (https://doi.org/10.1016/j.placenta.2010.08.011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Braun JE, Truffault V, Boland A, Huntzinger E, Chang CT, Haas G, Weichenrieder O, Coles M & Izaurralde E 2012 A direct interaction between DCP1 and XRN1 couples mRNA decapping to 5′ exonucleolytic degradation. Nature Structural and Molecular Biology 19 13241331. (https://doi.org/10.1038/nsmb.2413)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Burton GJ, Jauniaux E & Charnock-Jones DS 2007 Human early placental development: potential roles of the endometrial glands. Placenta 28 (Supplement A) S64S69. (https://doi.org/10.1016/j.placenta.2007.01.007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Cai M, Kolluru GK & Ahmed A 2017 Small molecule, big prospects: microRNA in pregnancy and its complications. Journal of Pregnancy 2017 6972732. (https://doi.org/10.1155/2017/6972732)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, Harris AL, Gleadle JM & Ragoussis J 2008 hsa-miR-210 is induced by hypoxia and is an independent prognostic factor in breast cancer. Clinical Cancer Research 14 13401348. (https://doi.org/10.1158/1078-0432.CCR-07-1755)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Caniggia I, Winter J, Lye SJ & Post M 2000 Oxygen and placental development during the first trimester: implications for the pathophysiology of pre-eclampsia. Placenta 21 S25S30. (https://doi.org/10.1053/plac.1999.0522)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Carter AM 2007 Animal models of human placentation – a review. Placenta 28 (Supplement A) S41S47. (https://doi.org/10.1016/j.placenta.2006.11.002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Cartwright JE, Fraser R, Leslie K, Wallace AE & James JL 2010 Remodelling at the maternal-fetal interface: relevance to human pregnancy disorders. Reproduction 140 803813. (https://doi.org/10.1530/REP-10-0294)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Castellano L & Stebbing J 2013 Deep sequencing of small RNAs identifies canonical and non-canonical miRNA and endogenous siRNAs in mammalian somatic tissues. Nucleic Acids Research 41 33393351. (https://doi.org/10.1093/nar/gks1474)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Catalanotto C, Cogoni C & Zardo G 2016 MicroRNA in control of gene expression: an overview of nuclear functions. International Journal of Molecular Sciences 17 E1712. (https://doi.org/10.3390/ijms17101712)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chaiwangyen W, Ospina-Prieto S, Photini SM, Schleussner E, Markert UR & Morales-Prieto DM 2015 Dissimilar microRNA-21 functions and targets in trophoblastic cell lines of different origin. International Journal of Biochemistry and Cell Biology 68 187196. (https://doi.org/10.1016/j.biocel.2015.08.018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Chakrabarty A, Tranguch S, Daikoku T, Jensen K, Furneaux H & Dey SK 2007 MicroRNA regulation of cyclooxygenase-2 during embryo implantation. PNAS 104 1514415149. (https://doi.org/10.1073/pnas.0705917104)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL & Loscalzo J 2009 MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metabolism 10 273284. (https://doi.org/10.1016/j.cmet.2009.08.015)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chang CW, Wakeland AK & Parast MM 2018 Trophoblast lineage specification, differentiation and their regulation by oxygen tension. Journal of Endocrinology 236 R43R56. (https://doi.org/10.1530/JOE-17-0402)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Chaouat G & Clark DA 2015 Are animal models useful or confusing in understanding the human feto-maternal relationship? A debate. Journal of Reproductive Immunology 108 5664. (https://doi.org/10.1016/j.jri.2014.10.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen Z, Li Y, Zhang H, Huang P & Luthra R 2010 Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression. Oncogene 29 43624368. (https://doi.org/10.1038/onc.2010.193)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cheong AW, Pang RT, Liu WM, Kottawatta KS, Lee KF & Yeung WS 2014 MicroRNA Let-7a and dicer are important in the activation and implantation of delayed implanting mouse embryos. Human Reproduction 29 750762. (https://doi.org/10.1093/humrep/det462)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Christie M, Boland A, Huntzinger E, Weichenrieder O & Izaurralde E 2013 Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182 proteins. Molecular Cell 51 360373. (https://doi.org/10.1016/j.molcel.2013.07.011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Colleoni F, Padmanabhan N, Yung HW, Watson ED, Cetin I, Tissot van Patot MC, Burton GJ & Murray AJ 2013 Suppression of mitochondrial electron transport chain function in the hypoxic human placenta: a role for miRNA-210 and protein synthesis inhibition. PLoS ONE 8 e55194. (https://doi.org/10.1371/journal.pone.0055194)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Concepcion CP, Bonetti C & Ventura A 2012 The microRNA-17-92 family of microRNA clusters in development and disease. Cancer Journal 18 262267. (https://doi.org/10.1097/PPO.0b013e318258b60a)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • de Rie D, Abugessaisa I, Alam T, Arner E, Arner P, Ashoor H, Astrom G, Babina M, Bertin N & Burroughs AM 2017 An integrated expression atlas of miRNAs and their promoters in human and mouse. Nature Biotechnology 35 872878. (https://doi.org/10.1038/nbt.3947)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Delorme-Axford E, Donker RB, Mouillet JF, Chu TJ, Bayer A, Ouyang YS, Wang TY, Stolz DB, Sarkar SN & Morelli AE 2013 Human placental trophoblasts confer viral resistance to recipient cells. PNAS 110 1204812053. (https://doi.org/10.1073/pnas.1304718110)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Demir R, Seval Y & Huppertz B 2007 Vasculogenesis and angiogenesis in the early human placenta. Acta Histochemica 109 257265. (https://doi.org/10.1016/j.acthis.2007.02.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Denli AM, Tops BB, Plasterk RH, Ketting RF & Hannon GJ 2004 Processing of primary microRNAs by the microprocessor complex. Nature 432 231235. (https://doi.org/10.1038/nature03049)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ding J, Huang F, Wu G, Han T, Xu F, Weng D, Wu C, Zhang X, Yao Y & Zhu X 2015 MiR-519d-3p suppresses invasion and migration of trophoblast cells via targeting MMP-2. PLoS ONE 10 e0120321. (https://doi.org/10.1371/journal.pone.0120321)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ding GC, Chen M, Wang YX, Rui C, Xu W, Ding HJ & Shi ZH 2016 MicroRNA-128a-induced apoptosis in HTR-8/SVneo trophoblast cells contributes to pre-eclampsia. Biomedicine and Pharmacotherapy 81 6370. (https://doi.org/10.1016/j.biopha.2016.03.040)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Donker RB, Mouillet JF, Nelson DM & Sadovsky Y 2007 The expression of Argonaute2 and related microRNA biogenesis proteins in normal and hypoxic trophoblasts. Molecular Human Reproduction 13 273279. (https://doi.org/10.1093/molehr/gam006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Doyle M, Badertscher L, Jaskiewicz L, Guttinger S, Jurado S, Hugenschmidt T, Kutay U & Filipowicz W 2013 The double-stranded RNA binding domain of human Dicer functions as a nuclear localization signal. RNA 19 12381252. (https://doi.org/10.1261/rna.039255.113)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ellwanger DC, Buttner FA, Mewes HW & Stumpflen V 2011 The sufficient minimal set of miRNA seed types. Bioinformatics 27 13461350. (https://doi.org/10.1093/bioinformatics/btr149)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Escudero CA, Herlitz K, Troncoso F, Acurio J, Aguayo C, Roberts JM, Truong G, Duncombe G, Rice G & Salomon C 2016 Role of extracellular vesicles and microRNAs on dysfunctional angiogenesis during preeclamptic pregnancies. Frontiers in Physiology 7 98. (https://doi.org/10.3389/fphys.2016.00098)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fabian MR & Sonenberg N 2012 The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nature Structural and Molecular Biology 19 586593. (https://doi.org/10.1038/nsmb.2296)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Farrokhnia F, Aplin JD, Westwood M & Forbes K 2014 MicroRNA regulation of mitogenic signaling networks in the human placenta. Journal of Biological Chemistry 289 3040430416. (https://doi.org/10.1074/jbc.M114.587295)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fu G, Brkic J, Hayder H & Peng C 2013a MicroRNAs in human placental development and pregnancy complications. International Journal of Molecular Sciences 14 55195544. (https://doi.org/10.3390/ijms14035519)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fu G, Ye G, Nadeem L, Ji L, Manchanda T, Wang Y, Zhao Y, Qiao J, Wang YL & Lye S 2013b MicroRNA-376c impairs transforming growth factor-beta and nodal signaling to promote trophoblast cell proliferation and invasion. Hypertension 61 864872. (https://doi.org/10.1161/HYPERTENSIONAHA.111.203489)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Fuziwara C & Kimura E 2015 Insights into regulation of the miR-17-92 cluster of miRNAs in cancer. Frontiers in Medicine 2 15. (https://doi.org/10.3389/fmed.2015.00064)

    • Search Google Scholar
    • Export Citation
  • Genbacev O, Joslin R, Damsky CH, Polliotti BM & Fisher SJ 1996 Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. Journal of Clinical Investigation 97 540550. (https://doi.org/10.1172/JCI118447)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Genbacev O, Zhou Y, Ludlow JW & Fisher SJ 1997 Regulation of human placental development by oxygen tension. Science 277 16691672. (https://doi.org/10.1126/science.277.5332.1669)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Geng Y, He J, Ding Y, Chen X, Zhou Y, Liu S, Liu X & Wang Y 2014 The differential expression of microRNAs between implantation sites and interimplantation sites in early pregnancy in mice and their potential functions. Reproductive Sciences 21 12961306. (https://doi.org/10.1177/1933719114525273)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Grigsby PL 2016 Animal models to study placental development and function throughout normal and dysfunctional human pregnancy. Seminars in Reproductive Medicine 34 1116. (https://doi.org/10.1055/s-0035-1570031)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gu Y, Bian Y, Xu X, Wang X, Zuo C, Meng J, Li H, Zhao S, Ning Y & Cao Y 2016 Downregulation of miR-29a/b/c in placenta accreta inhibits apoptosis of implantation site intermediate trophoblast cells by targeting MCL1. Placenta 48 1319. (https://doi.org/10.1016/j.placenta.2016.09.017)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ha M & Kim VN 2014 Regulation of microRNA biogenesis. Nature Reviews Molecular Cell Biology 15 509524. (https://doi.org/10.1038/nrm3838)

  • Hackmon R, Pinnaduwage L, Zhang J, Lye SJ, Geraghty DE & Dunk CE 2017 Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition. American Journal of Reproductive Immunology 77 e12643. (https://doi.org/10.1111/aji.12643)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Han J, Lee Y, Yeom KH, Kim YK, Jin H & Kim VN 2004 The Drosha-DGCR8 complex in primary microRNA processing. Genes and Development 18 30163027. (https://doi.org/10.1101/gad.1262504)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Havens MA, Reich AA & Hastings ML 2014 Drosha promotes splicing of a pre-microRNA-like alternative exon. PLoS Genetics 10 e1004312. (https://doi.org/10.1371/journal.pgen.1004312)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hu SJ, Ren G, Liu JL, Zhao ZA, Yu YS, Su RW, Ma XH, Ni H, Lei W & Yang ZM 2008 MicroRNA expression and regulation in mouse uterus during embryo implantation. Journal of Biological Chemistry 283 2347323484. (https://doi.org/10.1074/jbc.M800406200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Hu TX, Wang G, Guo XJ, Sun QQ, He P, Gu H, Huang Y, Gao L & Ni X 2016 MiR 20a,-20b and -200c are involved in hydrogen sulfide stimulation of VEGF production in human placental trophoblasts. Placenta 39 101110. (https://doi.org/10.1016/j.placenta.2016.01.019)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huntzinger E & Izaurralde E 2011 Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nature Reviews Genetics 12 99110. (https://doi.org/10.1038/nrg2936)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huppertz B & Peeters LL 2005 Vascular biology in implantation and placentation. Angiogenesis 8 157167. (https://doi.org/10.1007/s10456-005-9007-8)

  • Inoue K, Hirose M, Inoue H, Hatanaka Y, Honda A, Hasegawa A, Mochida K & Ogura A 2017 The rodent-specific microRNA cluster within the Sfmbt2 gene is imprinted and essential for placental development. Cell Reports 19 949956. (https://doi.org/10.1016/j.celrep.2017.04.018)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ipsaro JJ & Joshua-Tor L 2015 From guide to target: molecular insights into eukaryotic RNA-interference machinery. Nature Structural and Molecular Biology 22 2028. (https://doi.org/10.1038/nsmb.2931)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Ito M, Sferruzzi-Perri AN, Edwards CA, Adalsteinsson BT, Allen SE, Loo TH, Kitazawa M, Kaneko-Ishino T, Ishino F & Stewart CL 2015 A trans-homologue interaction between reciprocally imprinted miR-127 and Rtl1 regulates placenta development. Development 142 24252430. (https://doi.org/10.1242/dev.121996)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ji L, Brkic J, Liu M, Fu G, Peng C & Wang YL 2013 Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Molecular Aspects of Medicine 34 9811023. (https://doi.org/10.1016/j.mam.2012.12.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ji L, Zhang L, Li Y, Guo L, Cao N, Bai Z, Song Y, Xu Z, Zhang J & Liu C 2017 MiR-136 contributes to pre-eclampsia through its effects on apoptosis and angiogenesis of mesenchymal stem cells. Placenta 50 102109. (https://doi.org/10.1016/j.placenta.2017.01.102)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jiang L, Long A, Tan L, Hong M, Wu J, Cai L & Li Q 2017a Elevated microRNA-520g in pre-eclampsia inhibits migration and invasion of trophoblasts. Placenta 51 7075. (https://doi.org/10.1016/j.placenta.2017.02.001)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jiang S, Teague AM, Tryggestad JB & Chernausek SD 2017b Role of microRNA-130b in placental PGC-1alpha/TFAM mitochondrial biogenesis pathway. Biochemical and Biophysical Research Communications 487 607612. (https://doi.org/10.1016/j.bbrc.2017.04.099)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Johnson MH & Ziomek CA 1981 Induction of polarity in mouse 8-cell blastomeres: specificity, geometry, and stability. Journal of Cell Biology 91 303308. (https://doi.org/10.1083/jcb.91.1.303)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Jonas S & Izaurralde E 2015 Towards a molecular understanding of microRNA-mediated gene silencing. Nature Reviews Genetics 16 421433. (https://doi.org/10.1038/nrg3965)

  • Kang H, Louie J, Weisman A, Sheu-Gruttadauria J, Davis-Dusenbery BN, Lagna G & Hata A 2012 Inhibition of microRNA-302 (miR-302) by bone morphogenetic protein 4 (BMP4) facilitates the BMP signaling pathway. Journal of Biological Chemistry 287 3865638664. (https://doi.org/10.1074/jbc.M112.390898)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kang YJ, Lees M, Matthews LC, Kimber SJ, Forbes K & Aplin JD 2015 MiR-145 suppresses embryo-epithelial juxtacrine communication at implantation by modulating maternal IGF1R. Journal of Cell Science 128 804814. (https://doi.org/10.1242/jcs.164004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kaufmann P & Castellucci M 1997 Extravillous trophoblasts in the human placenta – a review. Trophoblast Research 10 2165. (https://doi.org/10.1016/S0143-4004(97)80079-3)

    • Search Google Scholar
    • Export Citation
  • Kaufmann P, Mayhew TM & Charnock-Jones DS 2004 Aspects of human fetoplacental vasculogenesis and angiogenesis. II. Changes during normal pregnancy. Placenta 25 114126. (https://doi.org/10.1016/j.placenta.2003.10.009)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kawamata T & Tomari Y 2010 Making RISC. Trends in Biochemical Sciences 35 368376. (https://doi.org/10.1016/j.tibs.2010.03.009)

  • Kim YK & Kim VN 2007 Processing of intronic microRNAs. EMBO Journal 26 775783. (https://doi.org/10.1038/sj.emboj.7601512)

  • Kim YK, Kim B & Kim VN 2016 Re-evaluation of the roles of DROSHA, export in 5, and DICER in microRNA biogenesis. PNAS 113 E1881E1889. (https://doi.org/10.1073/pnas.1602532113)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Knofler M 2010 Critical growth factors and signalling pathways controlling human trophoblast invasion. International Journal of Developmental Biology 54 269280. (https://doi.org/10.1387/ijdb.082769mk)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kolahi KS, Valent AM & Thornburg KL 2017 Cytotrophoblast, not syncytiotrophoblast, dominates glycolysis and oxidative phosphorylation in human term placenta. Scientific Reports 7 42941. (https://doi.org/10.1038/srep42941)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Krawczynski K, Mishima T, Huang X & Sadovsky Y 2016 Intact feto-placental growth in microRNA-210 deficient mice. Placenta 47 113115. (https://doi.org/10.1016/j.placenta.2016.09.007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M & Stoffel M 2005 Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438 685689. (https://doi.org/10.1038/nature04303)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, Davuluri R, Liu CG, Croce CM & Negrini M 2007 A microRNA signature of hypoxia. Molecular and Cellular Biology 27 18591867. (https://doi.org/10.1128/MCB.01395-06)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kumar P, Luo Y, Tudela C, Alexander JM & Mendelson CR 2013 The c-Myc-regulated microRNA-17~92 (miR-17~92) and miR-106a~363 clusters target hCYP19A1 and hGCM1 to inhibit human trophoblast differentiation. Molecular and Cellular Biology 33 17821796. (https://doi.org/10.1128/MCB.01228-12)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lee RC, Feinbaum RL & Ambros V 1993 The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75 843854. (https://doi.org/10.1016/0092-8674(93)90529-Y)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Levy R, Smith SD, Chandler K, Sadovsky Y & Nelson M 2000 Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor. American Journal of Physiology: Cell Physiology 278 C982C988. (https://doi.org/10.1152/ajpcell.2000.278.5.C982)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Li P, Guo W, Du L, Zhao J, Wang Y, Liu L, Hu Y & Hou Y 2013 microRNA-29b contributes to pre-eclampsia through its effects on apoptosis, invasion and angiogenesis of trophoblast cells. Clinical Science 124 2740. (https://doi.org/10.1042/CS20120121)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Liang CY, Wang LJ, Chen CP, Chen LF, Chen YH & Chen H 2010 GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta. Biology of Reproduction 83 387395. (https://doi.org/10.1095/biolreprod.110.083915)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lipchina I, Elkabetz Y, Hafner M, Sheridan R, Mihailovic A, Tuschl T, Sander C, Studer L & Betel D 2011 Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response. Genes and Development 25 21732186. (https://doi.org/10.1101/gad.17221311)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lu J, Zhang S, Nakano H, Simmons DG, Wang S, Kong S, Wang Q, Shen L, Tu Z & Wang W 2013 A positive feedback loop involving Gcm1 and Fzd5 directs chorionic branching morphogenesis in the placenta. PLoS Biology 11 e1001536. (https://doi.org/10.1371/journal.pbio.1001536)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Luo L, Ye G, Nadeem L, Fu G, Yang BB, Honarparvar E, Dunk C, Lye S & Peng C 2012 MicroRNA-378a-5p promotes trophoblast cell survival, migration and invasion by targeting Nodal. Journal of Cell Science 125 31243132. (https://doi.org/10.1242/jcs.096412)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Luo R, Wang Y, Xu P, Cao G, Zhao Y, Shao X, Li YX, Chang C, Peng C & Wang YL 2016 Hypoxia-inducible miR-210 contributes to preeclampsia via targeting thrombospondin type I domain containing 7A. Scientific Reports 6 19588. (https://doi.org/10.1038/srep19588)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lyall F, Robson SC & Bulmer JN 2013 Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome. Hypertension 62 10461054. (https://doi.org/10.1161/HYPERTENSIONAHA.113.01892)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Maltepe E & Fisher SJ 2015 Placenta: the forgotten organ. Annual Review of Cell and Developmental Biology 31 523552. (https://doi.org/10.1146/annurev-cellbio-100814-125620)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Maltepe E, Bakardjiev AI & Fisher SJ 2010 The placenta: transcriptional, epigenetic, and physiological integration during development. Journal of Clinical Investigation 120 10161025. (https://doi.org/10.1172/JCI41211)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Manaster I, Goldman-Wohl D, Greenfield C, Nachmani D, Tsukerman P, Hamani Y, Yagel S & Mandelboim O 2012 MiRNA-mediated control of HLA-G expression and function. PLoS ONE 7 e33395. (https://doi.org/10.1371/journal.pone.0033395)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meijer HA, Kong YW, Lu WT, Wilczynska A, Spriggs RV, Robinson SW, Godfrey JD, Willis AE & Bushell M 2013 Translational repression and eIF4A2 activity are critical for microRNA-mediated gene regulation. Science 340 8285. (https://doi.org/10.1126/science.1231197)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miao L, Yao H, Li C, Pu M, Yao X, Yang H, Qi X, Ren J & Wang Y 2016 A dual inhibition: microRNA-552 suppresses both transcription and translation of cytochrome P450 2E1. Biochimica et Biophysica Acta 1859 650662. (https://doi.org/10.1016/j.bbagrm.2016.02.016)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miller RK, Genbacev O, Turner MA, Aplin JD, Caniggia I & Huppertz B 2005 Human placental explants in culture: approaches and assessments. Placenta 26 439448. (https://doi.org/10.1016/j.placenta.2004.10.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moffett A & Loke C 2006 Immunology of placentation in eutherian mammals. Nature Reviews Immunology 6 584594. (https://doi.org/10.1038/nri1897)

  • Morales-Prieto DM, Ospina-Prieto S, Schmidt A, Chaiwangyen W & Markert UR 2014 Elsevier trophoblast research award lecture: origin, evolution and future of placenta miRNAs. Placenta 35 S39S45. (https://doi.org/10.1016/j.placenta.2013.11.017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mori M, Bogdan A, Balassa T, Csabai T & Szekeres-Bartho J 2016 The decidua-the maternal bed embracing the embryo-maintains the pregnancy. Seminars in Immunopathology 38 635649. (https://doi.org/10.1007/s00281-016-0574-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moser G, Gauster M, Orendi K, Glasner A, Theuerkauf R & Huppertz B 2010 Endoglandular trophoblast, an alternative route of trophoblast invasion? Analysis with novel confrontation co-culture models. Human Reproduction 25 11271136. (https://doi.org/10.1093/humrep/deq035)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Moser G, Weiss G, Gauster M, Sundl M & Huppertz B 2015 Evidence from the very beginning: endoglandular trophoblasts penetrate and replace uterine glands in situ and in vitro. Human Reproduction 30 27472757. (https://doi.org/10.1093/humrep/dev266)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mouillet JF, Chu T, Hubel CA, Nelson DM, Parks WT & Sadovsky Y 2010 The levels of hypoxia-regulated microRNAs in plasma of pregnant women with fetal growth restriction. Placenta 31 781784. (https://doi.org/10.1016/j.placenta.2010.07.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mouillet JF, Chu T & Sadovsky Y 2011 Expression patterns of placental microRNAs. Birth Defects Research Part A: Clinical and Molecular Teratology 91 737743. (https://doi.org/10.1002/bdra.20782)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mouillet JF, Ouyang YS, Bayer A, Coyne CB & Sadovsky Y 2014 The role of trophoblastic microRNAs in placental viral infection. International Journal of Developmental Biology 58 281289. (https://doi.org/10.1387/ijdb.130349ys)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Mouillet JF, Ouyang Y, Coyne CB & Sadovsky Y 2015 MicroRNAs in placental health and disease. American Journal of Obstetrics and Gynecology 213 S163S172. (https://doi.org/10.1016/j.ajog.2015.05.057)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Muralimanoharan S, Maloyan A, Mele J, Guo C, Myatt LG & Myatt L 2012 MIR-210 modulates mitochondrial respiration in placenta with preeclampsia. Placenta 33 816823. (https://doi.org/10.1016/j.placenta.2012.07.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Muralimanoharan S, Maloyan A & Myatt L 2016 Mitochondrial function and glucose metabolism in the placenta with gestational diabetes mellitus: role of miR-143. Clinical Science 130 931941. (https://doi.org/10.1042/CS20160076)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Murray AJ 2012 Oxygen delivery and fetal-placental growth: beyond a question of supply and demand? Placenta 33 (Supplement 2) e16e22. (https://doi.org/10.1016/j.placenta.2012.06.006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Nadeem U, Ye G, Salem M & Peng C 2014 MicroRNA-378a-5p targets cyclin G2 to inhibit fusion and differentiation in BeWo cells. Biology of Reproduction 91 76. (https://doi.org/10.1095/biolreprod.114.119065)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Niu ZR, Han T, Sun XL, Luan LX, Gou WL & Zhu XM 2018 MicroRNA-30a-3p is overexpressed in the placentas of patients with preeclampsia and affects trophoblast invasion and apoptosis by its effects on IGF-1. American Journal of Obstetrics and Gynecology 218 249 e241.e12e249.e12 (https://doi.org/10.1016/j.ajog.2017.11.568)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Noris M, Perico N & Remuzzi G 2005 Mechanisms of disease: pre-eclampsia. Nature Clinical Practice Nephrology 1 98114; quiz 120. (https://doi.org/10.1038/ncpneph0035)

  • Nosi U, Lanner F, Huang T & Cox B 2017 Overexpression of trophoblast stem cell-enriched microRNAs promotes trophoblast fate in embryonic stem cells. Cell Reports 19 11011109. (https://doi.org/10.1016/j.celrep.2017.04.040)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ouyang Y, Mouillet JF, Coyne CB & Sadovsky Y 2014 Review: placenta-specific microRNAs in exosomes good things come in nano-packages. Placenta 35 S69S73. (https://doi.org/10.1016/j.placenta.2013.11.002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Paikari A, C DB, Saw D & Blelloch R 2017 The eutheria-specific miR-290 cluster modulates placental growth and maternal-fetal transport. Development 144 37313743. (https://doi.org/10.1242/dev.151654)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pan Q, Niu H, Cheng L, Li X, Zhang Q & Ning Y 2017 Invasion of trophoblast cell lines is inhibited by miR-93 via MMP-2. Placenta 53 4853. (https://doi.org/10.1016/j.placenta.2017.03.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Papandreou I, Cairns RA, Fontana L, Lim AL & Denko NC 2006 HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metabolism 3 187197. (https://doi.org/10.1016/j.cmet.2006.01.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pringle KG, Kind KL, Sferruzzi-Perri AN, Thompson JG & Roberts CT 2010 Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy. Human Reproduction Update 16 415431. (https://doi.org/10.1093/humupd/dmp046)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rajagopalan S, Bryceson YT, Kuppusamy SP, Geraghty DE, van der Meer A, Joosten I & Long EO 2006 Activation of NK cells by an endocytosed receptor for soluble HLA-G. PLoS Biology 4 e9. (https://doi.org/10.1371/journal.pbio.0040009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ratsep MT, Felker AM, Kay VR, Tolusso L, Hofmann AP & Croy BA 2015 Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis. Reproduction 149 R91R102. (https://doi.org/10.1530/REP-14-0271)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Red-Horse K, Zhou Y, Genbacev O, Prakobphol A, Foulk R, McMaster M & Fisher SJ 2004 Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. Journal of Clinical Investigation 114 744754. (https://doi.org/10.1172/JCI200422991)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Regnault TR, Galan HL, Parker TA & Anthony RV 2002 Placental development in normal and compromised pregnancies – a review. Placenta 23 (Supplement A) S119S129. (https://doi.org/10.1053/plac.2002.0792)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Revel A, Achache H, Stevens J, Smith Y & Reich R 2011 MicroRNAs are associated with human embryo implantation defects. Human Reproduction 26 28302840. (https://doi.org/10.1093/humrep/der255)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Reynolds LP & Redmer DA 2001 Angiogenesis in the placenta. Biology of Reproduction 64 10331040. (https://doi.org/10.1095/biolreprod64.4.1033)

  • Robertson SA & Moldenhauer LM 2014 Immunological determinants of implantation success. International Journal of Developmental Biology 58 205217. (https://doi.org/10.1387/ijdb.140096sr)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Robertson SA, Zhang B, Chan H, Sharkey DJ, Barry SC, Fullston T & Schjenken JE 2017 MicroRNA regulation of immune events at conception. Molecular Reproduction and Development 84 914925. (https://doi.org/10.1002/mrd.22823)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rossant J & Cross JC 2001 Placental development: lessons from mouse mutants. Nature Reviews Genetics 2 538548. (https://doi.org/10.1038/35080570)

  • Ruby JG, Jan CH & Bartel DP 2007 Intronic microRNA precursors that bypass Drosha processing. Nature 448 8386. (https://doi.org/10.1038/nature05983)

  • Schjenken JE, Zhang B, Chan HY, Sharkey DJ, Fullston T & Robertson SA 2016 miRNA regulation of immune tolerance in early pregnancy. American Journal of Reproductive Immunology 75 272280. (https://doi.org/10.1111/aji.12490)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schmidt A, Morales-Prieto DM, Pastuschek J, Frohlich K & Markert UR 2015 Only humans have human placentas: molecular differences between mice and humans. Journal of Reproductive Immunology 108 6571. (https://doi.org/10.1016/j.jri.2015.03.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Seitz H, Royo H, Bortolin ML, Lin SP, Ferguson-Smith AC & Cavaille J 2004 A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain. Genome Research 14 17411748. (https://doi.org/10.1101/gr.2743304)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Su MT, Tsai PY, Tsai HL, Chen YC & Kuo PL 2017 miR-346 and miR-582-3p-regulated EG-VEGF expression and trophoblast invasion via matrix metalloproteinases 2 and 9. Biofactors 43 210219. (https://doi.org/10.1002/biof.1325)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sun M, Chen H, Liu J, Tong C & Meng T 2015 MicroRNA-34a inhibits human trophoblast cell invasion by targeting MYC. BMC Cell Biology 16 21. (https://doi.org/10.1186/s12860-015-0068-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Szekeres-Bartho J 2002 Immunological relationship between the mother and the fetus. International Reviews of Immunology 21 471495. (https://doi.org/10.1080/08830180215017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Takahashi H, Ohkuchi A, Kuwata T, Usui R, Baba Y, Suzuki H, Chaw Kyi TT, Matsubara S, Saito S & Takizawa T 2017 Endogenous and exogenous miR-520c-3p modulates CD44-mediated extravillous trophoblast invasion. Placenta 50 2531. (https://doi.org/10.1016/j.placenta.2016.12.016)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Truesdell SS, Mortensen RD, Seo M, Schroeder JC, Lee JH, LeTonqueze O & Vasudevan S 2012 MicroRNA-mediated mRNA translation activation in quiescent cells and oocytes involves recruitment of a nuclear microRNP. Scientific Reports 2 842. (https://doi.org/10.1038/srep00842)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Valinezhad Orang A, Safaralizadeh R & Kazemzadeh-Bavili M 2014 Mechanisms of miRNA-mediated gene regulation from common downregulation to mRNA-specific upregulation. International Journal of Genomics 2014 970607. (https://doi.org/10.1155/2014/970607)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vasudevan S 2012 Posttranscriptional upregulation by microRNAs. Wiley Interdisciplinary Reviews: RNA 3 311330. (https://doi.org/10.1002/wrna.121)

  • Viswanathan SR, Mermel CH, Lu J, Lu CW, Golub TR & Daley GQ 2009 microRNA expression during trophectoderm specification. PLoS ONE 4 e6143. (https://doi.org/10.1371/journal.pone.0006143)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wakeland AK, Soncin F, Moretto-Zita M, Chang CW, Horii M, Pizzo D, Nelson KK, Laurent LC & Parast MM 2017 Hypoxia directs human extravillous trophoblast differentiation in a hypoxia-inducible factor-dependent manner. American Journal of Pathology 187 767780. (https://doi.org/10.1016/j.ajpath.2016.11.018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wang Y & Zhao S 2010 Integrated systems physiology: from molecules to function to disease. In Vascular Biology of the Placenta. San Rafael (CA): Morgan & Claypool Life Sciences.

    • Search Google Scholar
    • Export Citation
  • Wang Y, Zhang Y, Wang H, Wang J, Zhang Y, Wang Y, Pan Z & Luo S 2014 Aberrantly up-regulated miR-20a in pre-eclampsic placenta compromised the proliferative and invasive behaviors of trophoblast cells by targeting forkhead box protein A1. International Journal of Biological Sciences 10 973982. (https://doi.org/10.7150/ijbs.9088)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang L, Wang HP, Wang Y & Wang J 2017 MicroRNA-195 is downregulated in the peripheral blood of pregnant women with pregnancy-induced hypertension and inhibits the trophoblast apoptosis through targeting iNOS. International Journal of Clinical and Experimental Medicine 10 716723.

    • Search Google Scholar
    • Export Citation
  • Wildman DE, Chen CY, Erez O, Grossman LI, Goodman M & Romero R 2006 Evolution of the mammalian placenta revealed by phylogenetic analysis. PNAS 103 32033208. (https://doi.org/10.1073/pnas.0511344103)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wooding FBP & Burton G 2008 Comparative Placentation: Structures, Functions and Evolution. Berlin: Springer.

  • Wu Z, Zhang W, Chen G, Cheng L, Liao J, Jia N, Gao Y, Dai H, Yuan J & Cheng L 2008 Combinatorial signals of activin/nodal and bone morphogenic protein regulate the early lineage segregation of human embryonic stem cells. Journal of Biological Chemistry 283 2499125002. (https://doi.org/10.1074/jbc.M803893200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wu H, Wang H, Liu M, Bai Y, Li YX, Ji L, Peng C, Yu Y & Wang YL 2016 MiR-195 participates in the placental disorder of preeclampsia via targeting activin receptor type-2B in trophoblastic cells. Journal of Hypertension 34 13711379. (https://doi.org/10.1097/HJH.0000000000000948)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xiao M, Li J, Li W, Wang Y, Wu F, Xi Y, Zhang L, Ding C, Luo H & Li Y 2016 MicroRNAs activate gene transcription epigenetically as an enhancer trigger. RNA Biology 14 13261334. (https://doi.org/10.1080/15476286.2015.1112487)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xie M, Li M, Vilborg A, Lee N, Shu MD, Yartseva V, Sestan N & Steitz JA 2013 Mammalian 5′-capped microRNA precursors that generate a single microRNA. Cell 155 15681580. (https://doi.org/10.1016/j.cell.2013.11.027)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xu RH, Chen X, Li DS, Li R, Addicks GC, Glennon C, Zwaka TP & Thomson JA 2002 BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nature Biotechnology 20 12611264. (https://doi.org/10.1038/nbt761)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xu W, San Lucas A, Wang Z & Liu Y 2014 Identifying microRNA targets in different gene regions. BMC Bioinformatics 15 (Supplement 7) S4. (https://doi.org/10.1186/1471-2105-15-S7-S4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yan T, Liu Y, Cui K, Hu B, Wang F & Zou L 2013 MicroRNA-126 regulates EPCs function: implications for a role of miR-126 in preeclampsia. Journal of Cellular Biochemistry 114 21482159. (https://doi.org/10.1002/jcb.24563)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yang JS & Lai EC 2011 Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Molecular Cell 43 892903. (https://doi.org/10.1016/j.molcel.2011.07.024)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yoda M, Kawamata T, Paroo Z, Ye X, Iwasaki S, Liu Q & Tomari Y 2010 ATP-dependent human RISC assembly pathways. Nature Structural and Molecular Biology 17 1723. (https://doi.org/10.1038/nsmb.1733)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Yu C, Shen K, Lin M, Chen P, Lin C, Chang GD & Chen H 2002 GCMa regulates the syncytin-mediated trophoblastic fusion. Journal of Biological Chemistry 277 5006250068. (https://doi.org/10.1074/jbc.M209316200)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Yu Y, Wang L, Liu T & Guan H 2015 MicroRNA-204 suppresses trophoblast-like cell invasion by targeting matrix metalloproteinase-9. Biochemical and Biophysical Research Communications 463 285291. (https://doi.org/10.1016/j.bbrc.2015.05.052)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang H, Kolb FA, Jaskiewicz L, Westhof E & Filipowicz W 2004 Single processing center models for human Dicer and bacterial RNase III. Cell 118 5768. (https://doi.org/10.1016/j.cell.2004.06.017)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang Y, Fei M, Xue G, Zhou Q, Jia Y, Li L, Xin H & Sun S 2012 Elevated levels of hypoxia-inducible microRNA-210 in pre-eclampsia: new insights into molecular mechanisms for the disease. Journal of Cellular and Molecular Medicine 16 249259. (https://doi.org/10.1111/j.1582-4934.2011.01291.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang J, Dunk C, Croy AB & Lye SJ 2016a To serve and to protect: the role of decidual innate immune cells on human pregnancy. Cell and Tissue Research 363 249265. (https://doi.org/10.1007/s00441-015-2315-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zhang M, Muralimanoharan S, Wortman AC & Mendelson CR 2016b Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia. PNAS 113 E7069E7076. (https://doi.org/10.1073/pnas.1607849113)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zheng GX, Ravi A, Gould GM, Burge CB & Sharp PA 2011 Genome-wide impact of a recently expanded microRNA cluster in mouse. PNAS 108 1580415809. (https://doi.org/10.1073/pnas.1112772108)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Zhu X, Yang Y, Han T, Yin G, Gao P, Ni Y, Su X, Liu Y & Yao Y 2015 Suppression of microRNA-18a expression inhibits invasion and promotes apoptosis of human trophoblast cells by targeting the estrogen receptor alpha gene. Molecular Medicine Reports 12 27012706. (https://doi.org/10.3892/mmr.2015.3724)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhu Y, Lu H, Huo Z, Ma Z, Dang J, Dang W, Pan L, Chen J & Zhong H 2016 MicroRNA-16 inhibits feto-maternal angiogenesis and causes recurrent spontaneous abortion by targeting vascular endothelial growth factor. Scientific Reports 6 35536. (https://doi.org/10.1038/srep35536)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zou Y, Jiang Z, Yu X, Zhang Y, Sun M, Wang W, Ge Z, De W & Sun L 2014 MiR-101 regulates apoptosis of trophoblast HTR-8/SVneo cells by targeting endoplasmic reticulum (ER) protein 44 during preeclampsia. Journal of Human Hypertension 28 610616. (https://doi.org/10.1038/jhh.2014.35)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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    Overview of canonical microRNA biogenesis and mechanism. Canonical miRNA biogenesis is both Drosha- and Dicer-dependent. Following transcription, the primary (pri-) miRNA is identified and cleaved by the endoribonuclease, Drosha, to produce the precursor (pre-) miRNA. Nuclear export of the pre-miRNA is facilitated by the Exportin 5/RanGTP transport system. Once in the cytoplasm, the pre-miRNA is subject to terminal loop cleavage by the endoribonuclease Dicer. After cleavage, the mature miRNA duplex is loaded into the Argonaute family of proteins and the passenger strand is degraded, forming the miRNA-induced silencing complex (miRISC). The gene regulatory power of cytoplasmic miRISC typically culminates in gene silencing by mediating induction of translation inhibition, mRNA poly(A) deadenylation and mRNA degradation via interaction at the 3′ untranslated region of target mRNA. After target association and following recruitment of GW182 and associated proteins into miRISC, translation initiation is inhibited, preventing nascent protein translation of the target mRNA molecule. It is hypothesized that miRISC-induced dissociation of the translation initiation complex, eIF4F, from the 5′ cap of mRNA and/or its functional disruption suppresses translation initiation. Interaction of GW182 with poly(A) binding proteins (PABPC) and poly(A) deadenylase complexes PAN2/3 and CCR4-NOT localizes the 3′ mRNA tail to the miRISC complex, promoting efficient target mRNA deadenylation. Complete poly(A) deadenylation leads to decapping-protein 2 (DCP2)-mediated mRNA decapping, exposing the mRNA to 5′–3′ degradation via the exoribonuclease XRN1.

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    MicroRNAs involved in placental development. Proper development and functioning of the placenta requires precise control of trophoblast proliferation, apoptosis, differentiation, cellular metabolism, as well as vasculogenesis/angiogenesis. Many miRNAs have been suggested to play a regulatory role in one or more of these processes and are listed in this Venn diagram.

  • Abdelfattah AM, Park C & Choi MY 2014 Update on non-canonical microRNAs. Biomolecular Concepts 5 275287. (https://doi.org/10.1515/bmc-2014-0012)

  • Alaiti MA, Ishikawa M, Masuda H, Simon DI, Jain MK, Asahara T & Costa MA 2012 Up-regulation of miR-210 by vascular endothelial growth factor in ex vivo expanded CD34+ cells enhances cell-mediated angiogenesis. Journal of Cellular and Molecular Medicine 16 24132421. (https://doi.org/10.1111/j.1582-4934.2012.01557.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alarcon CR, Lee H, Goodarzi H, Halberg N & Tavazoie SF 2015 N6-methyladenosine marks primary microRNAs for processing. Nature 519 482485. (https://doi.org/10.1038/nature14281)

  • Ameres SL & Zamore PD 2013 Diversifying microRNA sequence and function. Nature Reviews Molecular Cell Biology 14 475488. (https://doi.org/10.1038/nrm3611)

  • Ameres S, Martinez J & Schroeder R 2007 Molecular basis for target RNA recognition and cleavage by human RISC. Cell 130 101112. (https://doi.org/10.1016/j.cell.2007.04.037)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ameres SL, Horwich MD, Hung JH, Xu J, Ghildiyal M, Weng Z & Zamore PD 2010 Target RNA-directed trimming and tailing of small silencing RNAs. Science 328 15341539. (https://doi.org/10.1126/science.1187058)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anin SR, Vince G & Quenby S 2004 Trophoblast invasion. Human Fertility 7 169174. (https://doi.org/10.1080/14647270400006911)

  • Anton L, Olarerin-George AO, Schwartz N, Srinivas S, Bastek J, Hogenesch JB & Elovitz MA 2013 miR-210 inhibits trophoblast invasion and is a serum biomarker for preeclampsia. American Journal of Pathology 183 14371445. (https://doi.org/10.1016/j.ajpath.2013.07.021)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Babiarz JE, Ruby JG, Wang Y, Bartel DP & Blelloch R 2008 Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. Genes and Development 22 27732785. (https://doi.org/10.1101/gad.1705308)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bayer A, Delorme-Axford E, Sleigher C, Frey TK, Trobaugh DW, Klimstra WB, Emert-Sedlak LA, Smithgall TE, Kinchington PR & Vadia S 2015 Human trophoblasts confer resistance to viruses implicated in perinatal infection. American Journal of Obstetrics and Gynecology 212 71.e171.e8. (https://doi.org/10.1016/j.ajog.2014.07.060)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Behm-Ansmant I, Rehwinkel J, Doerks T, Stark A, Bork P & Izaurralde E 2006 MRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes and Development 20 18851898. (https://doi.org/10.1101/gad.1424106)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Benhamed M, Herbig U, Ye T, Dejean A & Bischof O 2012 Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells. Nature Cell Biology 14 266275. (https://doi.org/10.1038/ncb2443)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bidarimath M, Khalaj K, Wessels JM & Tayade C 2014 MicroRNAs, immune cells and pregnancy. Cellular and Molecular Immunology 11 538547. (https://doi.org/10.1038/cmi.2014.45)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bilban M, Tauber S, Haslinger P, Pollheimer J, Saleh L, Pehamberger H, Wagner