Nongenomic ERα-AMPK Signaling Regulates Sex-Dependent Bcrp Transport Activity at the Blood-Brain Barrier.

The blood-brain barrier (BBB) is an extensive capillary network that protects the brain from environmental and metabolic toxins while limiting drug delivery to the central nervous system (CNS). The ATP-binding cassette transporter breast cancer resistance protein (Bcrp) reduces drug delivery across the BBB by actively transporting its clinical substrates back into peripheral circulation before their entry into the CNS compartment. 17β-Estradiol (E2)-elicited changes in Bcrp transport activity and expression have been documented previously.

A Novel Mouse Model to Analyze Non-Genomic ERα Physiological Actions.

Nongenomic effects of estrogen receptor α (ERα) signaling have been described for decades. Several distinct animal models have been generated previously to analyze the nongenomic ERα signaling (eg, membrane-only ER, and ERαC451A). However, the mechanisms and physiological processes resulting solely from nongenomic signaling are still poorly understood.

Peri- and Postpubertal Estrogen Exposures of Female Mice Optimize Uterine Responses Later in Life.

At birth, all female mice, including those that either lack estrogen receptor α (ERα-knockout) or that express mutated forms of ERα (AF2ERKI), have a hypoplastic uterus. However, uterine growth and development that normally accompany pubertal maturation does not occur in ERα-knockout or AF2ERKI mice, indicating ERα-mediated estrogen (E2) signaling is essential for this process. Mice that lack Cyp19 (aromatase knockout, ArKO mice), an enzyme critical for E2 synthesis, are unable to make E2 and lack pubertal uterine development.

Oviductal Retention of Embryos in Female Mice Lacking Estrogen Receptor α in the Isthmus and the Uterus.

Estrogen receptor α (ESR1; encoded by Esr1) is a crucial nuclear transcription factor for female reproduction and is expressed throughout the female reproductive tract. To assess the function of ESR1 in reproductive tissues without confounding effects from a potential developmental defect arising from global deletion of ESR1, we generated a mouse model in which Esr1 was specifically ablated during postnatal development. To accomplish this, a progesterone receptor Cre line (PgrCre) was bred with Esr1f/f mice to create conditional knockout of Esr1 in reproductive tissues (called PgrCreEsr1KO mice) beginning around 6 days after birth.

A distal super enhancer mediates estrogen-dependent mouse uterine-specific gene transcription of ().

Insulin-like growth factor 1 (IGF1) is primarily synthesized in and secreted from the liver; however, estrogen (E2), through E2 receptor α (ERα), increases uterine mRNA levels. Previous ChIP-seq analyses of the murine uterus have revealed a potential enhancer region distal from the transcription start site (TSS) with multiple E2-dependent ERα-binding regions. Here, we show E2-dependent super enhancer-associated characteristics and suggest contact between the distal enhancer and the TSS.

Negative elongation factor is essential for endometrial function.

Pausing of RNA polymerase II (Pol II) during early transcription, mediated by the negative elongation factor (NELF) complex, allows cells to coordinate and appropriately respond to signals by modulating the rate of transcriptional pause release. Promoter proximal enrichment of Pol II occurs at uterine genes relevant to reproductive biology; thus, we hypothesized that pausing might impact endometrial response by coordinating hormonal signals involved in establishing and maintaining pregnancy. We deleted the NELF-B subunit in the mouse uterus using PgrCre (NELF-B UtcKO).

N-terminal transactivation function, AF-1, of estrogen receptor alpha controls obesity through enhancement of energy expenditure.

Objective: Studies using the estrogen receptor alpha (ERα) knock-out (αERKO) mice have demonstrated that ERα plays a crucial role in various estrogen-mediated metabolic regulations. ERα is a ligand dependent transcription regulator and its activity is regulated by estrogenic compounds. ERα consists of two transcriptional activation domains, AF-1 and AF-2.

Juxtacrine Activity of Estrogen Receptor α in Uterine Stromal Cells is Necessary for Estrogen-Induced Epithelial Cell Proliferation.

Aberrant regulation of uterine cell growth can lead to endometrial cancer and infertility. To understand the molecular mechanisms of estrogen-induced uterine cell growth, we removed the estrogen receptor α (Esr1) from mouse uterine stromal cells, where the embryo is implanted during pregnancy. Without ESR1 in neighboring stroma cells, epithelial cells that line the inside of the uterus are unable to grow due to a lack of growth factors secreted from adjacent stromal cells.

Role of ERα in Mediating Female Uterine Transcriptional Responses to IGF1.

Estrogen (E2) signaling through its nuclear receptor, E2 receptor α (ERα) increases insulinlike growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor. Directly administering IGF1 results in similar biological and transcriptional uterine responses. Our studies using global ERα-null mice demonstrated a loss of uterine biological responses of the uterus to E2 or IGF1 treatment, while maintaining transcriptional responses to IGF1.