A novel mouse model to analyze non-genomic ERα physiological actions

Abstract Non-genomic effects of estrogen receptor α (ERα) signaling have been described for decades. Several distinct animal models have been generated previously to analyze the non-genomic ERα signaling (e.g., MOER, ERαC451A). However, the mechanisms and physiological processes resulting solely from non-genomic signaling are still poorly understood. Herein, we describe a novel mouse model for analyzing non-genomic ERα actions named H2NES knock-in (KI). H2NES ERα possesses a nuclear export signal (NES) in the hinge region of ERα protein resulting in exclusive cytoplasmic localization that involves only the non-genomic action but not nuclear genomic actions. We generated H2NESKI mice by homologous recombination method and have characterized the phenotypes. H2NESKI homozygote mice possess almost identical phenotypes with ERα null mice except for the vascular activity on reendothelialization. We conclude that ERα mediated non-genomic estrogenic signaling alone is insufficient to control most estrogen-mediated endocrine physiological responses; however, there could be some physiological responses that are non-genomic action dominant. H2NESKI mice have been deposited in the repository at Jax (Stock No: 032176). These mice should be useful for analyzing non-genomic estrogenic responses and could expand analysis along with other ERα mutant mice lacking membrane-bound ERα. We expect the H2NESKI mouse model to aid our understanding of ERα-mediated non-genomic physiological responses. Additionally, as an in vivo model for evaluating the non-genomic action of various estrogenic agents.