Developmental phenotype of a membrane only estrogen receptor α (MOER) mouse

Abstract

Estrogen receptors (ERs) α and β exist as nuclear, cytoplasmic, and membrane cellular pools in a wide variety of organs. The relative contributions of each ERα 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 ERα at the plasma membrane (MOER). Cells isolated from many organs showed membrane only localized E domain of ERα and no other receptor pools. Liver cells from MOER and wild type mice responded to 17-β-estradiol (E2) with comparable activation of ERK and phosphatidylinositol 3-kinase, not seen in cells from ERαKO 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 ERαKO mice showed multiple hemorrhagic cysts and no corpus luteum, and the mammary gland development in both MOER and ERαKO 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 ERα and is not rescued by membrane ERα domain expression alone.