Consequences of non-classical ERα signaling in brain
Ovarian estrogens exert critically important actions in hypothalamic neurons to regulate ovulatory cyclicity, reproductive behaviors, and energy homeostasis. Estrogen receptor alpha (ERα) appears to mediate most of these effects, as disruption of ER signaling leads to infertility and metabolic syndrome. ER signaling mechanisms may include classical genotropic effects mediated by direct binding of receptor dimers to DNA, non-classical genotropic effects involving tethering of ERs to other transcription factors, and non-classical non-genotropic actions mediated by cytoplasmic ERs coupled to membrane-initiated signal transduction pathways. Our studies make use of novel ER mutant mouse models to ascertain the cellular mechanisms by which ERα mediates E2 effects on these physiological and behavioral processes. We have utilized a novel mutant ER knock-in mouse model, which confers non-classical genotropic and non-genotropic signaling in the absence of classical signaling, to determine that non-classical ER signaling can convey E2 effects integral to homeostatic feedback control of reproductive hormone secretions, as well as E2 actions governing paracopulatory behavior and body weight regulation. Supported by NIH P50 HD44405 and NIH P01 HD21921.