Abstract
Concerted actions of estrogen and progesterone via their cognate receptors orchestrate changes in the uterine tissue, regulating implantation during early pregnancy. The uterine stromal cells undergo steroid-dependent differentiation into morphologically and functionally distinct decidual cells, which support embryonic growth and survival. The hormone-regulated pathways underlying this unique cellular transformation are not fully understood. Previous studies in the mouse revealed that, following embryo attachment, de novo synthesis of estrogen by the decidual cells is critical for stromal differentiation. In this study we report that Fos-related antigen 1 (FRA-1), a member of the Fos family of transcription factors, is a downstream target of regulation by intrauterine estrogen. FRA-1 expression was localized in the differentiating uterine stromal cells surrounding the implanted embryo. Attenuation of estrogen receptor α (Esr1) expression by siRNA mediated silencing in primary uterine stromal cells suppressed FRA-1 expression. Furthermore, chromatin immunoprecipitation demonstrated direct recruitment of ESR1 to an estrogen response element in the Fra-1 promoter. Down-regulation of Fra-1 expression during in vitro decidualization blocked stromal differentiation and resulted in a marked decrease in stromal cell migration. Interestingly, FRA-1 controls the expression of matrix metalloproteinases MMP9 and MMP13, which are critical modulators of stromal extracellular matrix remodeling. Collectively, these results suggest that FRA-1, induced in response to estrogen signaling via ESR1, is a key regulator of stromal differentiation and remodeling during early pregnancy.
Highlights
Intrauterine estrogen plays a critical role in differentiation of endometrial stromal cells during decidualization
In this study we report that Fos-related antigen 1 (FRA-1), a member of the Fos family of transcription factors, is a downstream target of regulation by intrauterine estrogen
These results suggest that FRA-1, induced in response to estrogen signaling via ESR1, is a key regulator of stromal differentiation and remodeling during early pregnancy
Summary
Intrauterine estrogen plays a critical role in differentiation of endometrial stromal cells during decidualization. FRA-1 controls the expression of matrix metalloproteinases MMP9 and MMP13, which are critical modulators of stromal extracellular matrix remodeling These results suggest that FRA-1, induced in response to estrogen signaling via ESR1, is a key regulator of stromal differentiation and remodeling during early pregnancy. As the decidua forms around the implanted embryo, the uterine endothelial cells proliferate to create an extensive vascular network, which is embedded in the decidua and critical for embryo development [5, 6] These morphological and functional changes in the pregnant uterus are regulated by the actions of the steroid hormones 17-estradiol (E) and progesterone (P), which act via their cognate nuclear receptors to control the expression of critical gene networks [7]. Consistent with this finding, treatment of these mice with letrozole, a specific inhibitor of P450 aromatase, blocked uterine stromal differentiation and impaired development of the angiogenic network in the stroma [10]
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