What's new in estrogen receptor action in the female reproductive tract

Abstract

Estrogen receptor alpha (ERα) is a critical player in development and function of the female reproductive system. Perturbations in ERα response can affect wide-ranging aspects of health in humans as well as in livestock and wildlife. Because of its long-known and broad impact, ERα mechanisms of action continue to be the focus on cutting-edge research efforts. Consequently, novel insights have greatly advanced understanding of every aspect of estrogen signaling. In this review, we attempt to briefly outline the current understanding of ERα mediated mechanisms in the context of the female reproductive system.

Keywords: estrogen receptors; gene expression; gene regulation; hormone action; uterus/endometrium.

Figure 1

Structures of ERα and ERβ protein with functional domains. Estrogen receptors ERα and ERβ share a conserved domain structure. The A/B domain, at the amino terminus (N) of the protein contains activation function 1 (AF1). The C domain binds to DNA motifs called estrogen responsive elements (EREs). The D domain is called the hinge region, and contributes to DNA binding specificity and nuclear localization of the ERs. The E domain is called the ligand binding domain because it interacts with estrogen, through an arrangement of 11 α helices (H1, and H3 through H12). H12 in this region of the receptor is critical to mediating transcriptional activation via activation function 2 (AF2). At the carboxy terminus (C) is the F domain. The % homology shared between ERα and ERβ in the C and E domains is shown.

Figure 2

Ligand-dependent and ligand-independent nuclear receptor mechanisms. The direct “classic” model of estrogen receptor (ER) action involves direct interaction between ER bound to estrogen (triangles) and ERE; the tethered pathway utilizes indirect “tethering” of ER to genes via interactions with other transcription factors (TF). “Nongenomic” signaling is initiated by membrane-localized receptors modulating extranuclear second messenger (SM) signaling pathways. Ligand-independent responses occur as a result of transduction of membrane receptor signaling, such as growth factors (GF), to nuclear ER. Reproduced, with permission, from Binder AK, Winuthayanon W, Hewitt SC, Couse JF & Korach KS (2015) Steroid receptors in the uterus and ovary. In Knobil and Neill's Physiology of Reproduction, 4^th Edn, pp 1099–1193. Eds TM Plant & AJ Zeleznik. Elsevier.

Figure 3

Model of chromatin dynamics in ER mediated transcription. FoxA1 interacts with chromatin, providing access for ER to nearby EREs. ER then interacts with transcriptional co-activators and chromatin modifying enzymes to open up transcription start sites (TSS) for RNA polymerase II (PolII), allowing initiation of transcription. Reproduced, with permission, from Wall EH, Hewitt SC, Case LK, Lin CY, Korach KS & Teuscher C (2014) The role of genetics in estrogen responses: a critical piece of an intricate puzzle. FASEB Journal 28 5042–5054.