Estrogen Receptor Alpha G525L Knock-In Mice

摘要

We have developed a 'knock-in' mouse model with a mutation (glycine 525 to leucine, G525L) in estrogen receptor alpha (ERalpha) that permits exogenous regulation of its ligand-induced signaling pathways, while not affecting ligand-independent signaling. The G525L ligand-binding pocket mutation significantly reduces ERalpha response to endogenous estrogens. These female estrogen non-responsive ERalpha knock-in (ENERKI) mice had immature and hypoplastic uterine and vaginal tissues and only developed rudimentary mammary gland ductal trees. Ovarian tissues contained no corpora lutea, indicating these mice are infertile due to anovulation. In addition, 89% of the ovaries contained large, hemorrhagic, cystic follicles. This physiology is consistent with a lack of estrogen negative feedback at the pituitary, which results in chronically elevated circulating levels of luteinizing hormone (LH). These phenotypes were similar to those of the ERalpha knock-out (alphaERKO) mice, confirming ligand-induced activation of ER is important in female reproductive tract development. Although the G525L mutation significantly reduces ERalpha response to endogenous estrogens, the ERalpha selective agonist propyl pyrazole triol (PPT) was still able to activate the mutant ERalpha in uterotrophic assays in the ENERKI females. Therefore, ERalpha signaling pathways can be regulated in developing mice as well as in adult animals with genetically induced mammary cancers through PPT administration or withdrawal.