Developmental Phenotype of a Membrane Only Estrogen Receptor α (MOER) Mouse

Estrogen receptors (ERs) alpha and beta exist as nuclear, cytoplasmic, and membrane cellular pools in a wide variety of organs. The relative contributions of each ER alpha pool to in vivo phenotypes resulting from estrogen signaling have not been determined. To address this, we generated a transgenic mouse expressing only a functional E domain of ER alpha at the plasma membrane (MOER). Cells isolated from many organs showed membrane only localized E domain of ER alpha and no other receptor pools. Liver cells from MOER and wild type mice responded to 17-beta-estradiol (E2) with comparable activation of ERK and phosphatidylinositol 3-kinase, not seen in cells from ER alpha KO mice. Mating the MOER female mice with proven male wild type breeders produced no pregnancies because the uterus and vagina of the MOER female mice were extremely atrophic. Ovaries of MOER and homozygous Strasbourg ER alpha KO mice showed multiple hemorrhagic cysts and no corpus luteum, and the mammary gland development in both MOER and ER alpha KO mice was rudimentary. Despite elevated serum E2 levels, serum LH was not suppressed, and prolactin levels were low in MOER mice. MOER and Strasbourg female mice showed plentiful abdominal visceral and other depots of fat and increased body weight compared to wild type mice despite comparable food consumption. These results provide strong evidence that the normal development and adult functions of important organs in female mice requires nuclear ER alpha and is not rescued by membrane ER alpha domain expression alone.