miR-145 suppresses embryo-epithelial juxtacrine communication at implantation by modulating maternal IGF1R

Abstract

Successful implantation requires the synchronization of viable embryonic development with endometrial receptivity. The mechanisms allowing for the initiation of crosstalk between the embryo and the endometrium remain elusive; however, recent studies have revealed that there are alterations in endometrial microRNAs (miRs) in women suffering repeated implantation failure and that one of the altered miRs is miR-145. We assessed the role of miR-145 and its target IGF1R, in early implantation. miR-145 overexpression and IGF1R knockdown were achieved in Ishikawa endometrial cells. Quantitative PCR, western blotting and 39UTR luciferase reporter assays confirmed that IGF1R is a direct target of miR-145 in the endometrium. Attachment of mouse embryos or IGF1-coated beads to endometrial epithelial cells was used to study the effects of altered miR-145 and/or IGF1R expression on early implantation events. miR-145 overexpression or specific reduction of IGF1R impaired attachment in both cases. An IGF1R target protector prevented the miR-145-mediated reduction in IGF1R and reversed the effect of miR-145 overexpression on attachment. The data demonstrate that miR-145 influences embryo attachment by reducing the level of IGF1R in endometrium.

Embryo–epithelium interactions during implantation at a glance

“…Accordingly, embryos that express miR-30d display increased adhesion to epithelial cells in vitro (Vilella et al, 2015). By contrast, there is evidence that a skewed miR profile in epithelial cells can impair receptivity (Kang et al, 2015).…”

“…It may be that there is a complex interplay between integrins and other cell surface factors. Indeed, a number of components of the uterine cell surface have functional roles in implantation and interact with αv integrins, including CD98 (officially known as SLC3A2) (Domínguez et al, 2010), the tetraspanin CD9 (Domínguez et al, 2010;Liu et al, 2006;Wynne et al, 2006), the dipeptidyl peptidase CD26 (officially known as DPP4) (Shimomura et al, 2006), the epidermal growth factor (EGF)-domaincontaining glycoprotein MFG-E8 (Schmitz et al, 2014), the IGF receptor (Fujita et al, 2013;Kang et al, 2015), galectin 3 (Lei et al, 2009;Yang et al, 2012) and galectin 15 (Lewis et al, 2007).…”

“…Present knowledge relies partly on in vitro models in which embryos, or trophoblastic spheroids derived from cell lines, primary tissue or embryonic stem cells, attach to 2D or 3D cultures of endometrial epithelium from either primary tissue or cell lines (Bentin-Ley et al, 1994;Boggavarapu et al, 2016;Hannan et al, 2009;Kang et al, 2015Kang et al, , 2014Lalitkumar et al, 2013;Lee et al, 2015;Singh and Aplin, 2015;Singh et al, 2010;Weimar et al, 2013). Recent observations of embryos attaching directly to cell-free surfaces demonstrate their self-organising potential (Deglincerti et al, 2016;Shahbazi et al, 2016).…”

Hsa-miR-30d, secreted by the human endometrium, is taken up by the pre-implantation embryo and might modify its transcriptome

“…miRNAs are secreted by cells and incorporated into microvesicles or associated with proteins that protect them from RNase degradation, endowing them with a long half-life (Turchinovich et al, 2011;Yoshizawa and Wong, 2013). These molecules have been implicated in the regulation of the WOI (Altmäe et al, 2010;Kuokkanen et al, 2010;Ng et al, 2013;Sha et al, 2011), decidualization (Estella et al, 2012a,b) and embryo development in humans (Mincheva-Nilsson and Baranov, 2010), and, more recently, embryo implantation in mice (Chen et al, 2015;Kang et al, 2015;Liu et al, 2013;Revel et al, 2011). In the present study, we aimed to elucidate the role of and mechanisms by which maternal miRNAs secreted into the EF act as transcriptomic regulators of the reprogramming of pre-implantation embryos by the maternal intrauterine environment.…”

miR-182 aids in receptive endometrium development in dairy goats by down-regulating PTN expression

“…Further studies reported that miR-30b, miR-30d, and -miR-494 are differentially expressed in pre-receptive and receptive endometria in human [10], suggesting that miRNAs played important roles in gene reprogramming during the formation of endometrial receptivity. In addition, miR-145 suppresses embryo-epithelial juxtacrine communication in the procession of embryo attachment by modulating the expression levels of IGF1R in endometria during WOI [11]. Together with its family members (miR-96 and miR-183), miR-182 was described in mouse neurosensory cells, specifically in the retina, inner ear, and dorsal root ganglia [12–14].…”