A Novel Mouse Model to Analyze Non-Genomic ER alpha Physiological Actions

Nongenomic effects of estrogen receptor alpha (ER alpha) signaling have been described for decades. Several distinct animal models have been generated previously to analyze the nongenomic ER alpha signaling (eg, membrane-only ER, and ER alpha C451A). However, the mechanisms and physiological processes resulting solely from nongenomic signaling are still poorly understood. Herein, we describe a novel mouse model for analyzing nongenomic ER alpha actions named H2NES knock-in (KI). H2NES ER alpha possesses a nuclear export signal (NES) in the hinge region of ER alpha protein resulting in exclusive cytoplasmic localization that involves only the nongenomic 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 ER alpha null mice except for the vascular activity on reendothelialization. We conclude that ER alpha-mediated nongenomic estrogenic signaling alone is insufficient to control most estrogen-mediated endocrine physiological responses; however, there could be some physiological responses that are nongenomic action dominant. H2NESKI mice have been deposited in the repository at Jax (stock no. 032176). These mice should be useful for analyzing nongenomic estrogenic responses and could expand analysis along with other ER alpha mutant mice lacking membrane-bound ER alpha. We expect the H2NESKI mouse model to aid our understanding of ER alpha-mediated nongenomic physiological responses and serve as an in vivo model for evaluating the nongenomic action of various estrogenic agents.