EMX2 Gene Expression in the Female Reproductive Tract and Aberrant Expression in the Endometrium of Patients with Endometriosis

Abstract

EMX2 is a transcription factor necessary for reproductive tract development. Sex steroids regulate endometrial HOXA10 expression, which in turn negatively regulates EMX2. In this study, we characterize menstrual cycle-dependent expression of EMX2 in endometrium from women with and without endometriosis. In the absence of endometriosis, EMX2 mRNA levels declined 50% in periimplantation endometrium compared with levels in the proliferative phase. To determine whether the decrease in endometrial EMX2 expression was regulated by endogenous endometrial HOXA10, primary endometrial stromal cells were transfected with an EMX2-reporter construct containing a HOXA10 binding site. Acting via this site, we observed HOXA10-mediated repression of reporter expression. In the endometrium of patients with endometriosis, unlike normal endometrium, EMX2 levels were not decreased in the periimplantation period. We have previously shown that up-regulation of HOXA10 in periimplantation endometrium fails to occur in women with endometriosis. To determine whether elevated endometrial EMX2 levels were due to failure of HOXA10-mediated transcriptional repression, secondary to low HOXA10 levels in endometriosis, we transfected stromal cells with HOXA10 antisense and an EMX2-reporter construct. Reporter expression was increased, indicating reversal of HOXA10-mediated transcriptional repression. Endometrial EMX2 expression is aberrant in women with endometriosis and is mediated by altered HOXA10 expression.

The Role ofHoxGenes in Female Reproductive Tract Development, Adult Function, and Fertility

“…Endometrial EMX2 expression is directly regulated by endogenous endometrial HOXA10. Normally EMX2 expression is downregulated in the peri-implantation period; however, this regulated expression fails in women with endometriosis (Troy et al 2003;Daftary and Taylor 2004). Further demonstrating the important role of this target gene, altering the endometrial Emx2 levels is not only associated with defective implantation, but also reduces litter size in mice .…”

The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review

“…Emx2 is also necessary for genitourinary tract development, as Emx2 mutant animals have Müllerian duct agenesis and die in utero due to urinary malformations [57]. In the adult, Emx2 expression drops to approximately 50% of normal levels in the periimplantation endometrium [56], an event which does not occur in women with endometriosis [58]. Furthermore, mice transfected with Emx2 cDNA in the periimplantation period have a 40% decrease in litter size, an effect mediated by diminished endometrial epithelial cell proliferation [59].…”

Gene Expression Profiling Reveals Putative HOXA10 Downstream Targets in the Periimplantation Mouse Uterus

“…17 Furthermore, efficient transfection and expression of an Escherichia coli lacZ reporter gene has been accomplished in intact human uteri ex vivo. 18,19 Thus, differential maternal expression of endometrial HOXA10 is essential for implantation as this transcription factor regulates the molecular switches that promote the appropriate endometrial receptivity.Because of the complexity of this system, it is not surprising that HOXA10 interacts with multiple targets, which in conjunction exert signal specificity and are functionally necessary. The purpose of this study was to establish and to define molecular profiles of those downstream targets of HOXA10 essential to the implantation process.…”