SIGNIFICANT PHENOTYPES IN A NUCLEAR ERa-ONLY (NOER) FEMALE MOUSE

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 338-357-Steroid Hormone Actions
Basic/Translational
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-338
Ali A Pedram1, Mahnaz Razandi2, Stephen R Hammes3, Michael Lewis4 and Ellis R Levin*5
1Univ of CA-Irvine, Long Beach, CA, 2Long Beach VAMC, Long Beach, CA, 3University of Rochester, Rochester, NY, 4Baylor College of Medicine, 5University of California-Irvine/Long Beach VAMC, Long Beach, CA
Both estrogen receptor isoforms are found in various cell compartments that presumably collaborate to produce the final actions on organ development and function. ERα is important for female mouse reproductive tract and mammary gland development/function, from the phenotypes of the ERαKO mouse. We showed the nuclear receptor is required for these functions (JBC, 2009) using a mouse (MOER) that lacks nuclear ERα. Whether membrane-localized ERα is also required is not established in-vivo. We therefore created a transgenic mouse, inserting by homologous recombination a palmitoylation point mutant (Cystine451Alanine) ERα construct into the esr1 locus of ES cells to generate mice. Hepatocytes from this mouse, for instance, show comparable nuclear ERα expression to wild type (WT) mice but no membrane-localized ERα, and no rapid signaling (ERK and PI3K-AKT) stimulated by estradiol, in contrast to WT mice cells. These mice are called nuclear-ERalpha only (NOER) mice. Phenotypically, pubertal homozygous NOER female mice are entirely infertile, from 20 encounters with proven breeder WT males. In contrast, heterozygous NOER or homozygous WT female mice showed comparable fecundity. Infertility in homozygous MOER female mice was explained by grossly abnormal ovaries lacking corpus lutea, compared to the normal morphology and size of heterozygote NOER and WT mouse ovaries. Mammary gland development in 10-12 week old, virgin WT and heterozygous NOER female mice was comparable, with appropriate ductal development. In contrast, the homozygous NOER females showed little ductal side-branching, indicating an important role for membrane ERα. This phenotype likely arises in part from lack of corpus lutea and hence progesterone production that is required for ductal side-branching in mammary gland (and for fertility). Hormone measurements are pending. Visceral fat deposition in the abdomen was markedly enhanced only in the homozygous female NOER mouse. Our results establish multiple strong phenotypes from the specific deletion of the membrane ERα pool. Thus, membrane ERα is required for normal female fertility, ovarian and mammary gland development and function, and suppression of fat maturation in mammals, working in conjunction with the nuclear ERα pool to promote these critical functions of the sex steroid.

Nothing to Disclose: AAP, MR, SRH, ML, ERL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NCI, VA
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