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

ABSTRACT: 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 ERalpha 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 ERalpha at the plasma membrane (MOER). Cells isolated from many organs showed membrane only localized E domain of ERalpha 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 ERalphaKO 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 ERalphaKO mice showed multiple hemorrhagic cysts and no corpus luteum, and the mammary gland development in both MOER and ERalphaKO 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 ERalpha and is not rescued by membrane ERalpha domain expression alone.

SUBMITTER: Pedram A

PROVIDER: S-EPMC2635032 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Pedram Ali A Razandi Mahnaz M Kim Jin K JK O'Mahony Fiona F Lee Eva Yhp EY Luderer Ulrike U Levin Ellis R ER

The Journal of biological chemistry 20081203 6

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 ERalpha 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 ERalpha at the plasma membrane (MOER). Cells isolated from many organs showed membrane only localized E domain of ERalpha and no other receptor pools. L ...[more]

PMID: 19054762

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Project description:Estrogen receptor-α (ESR1) is an important transcriptional regulator in the mammalian oviduct, however ESR1-dependent regulation of the transcriptome of this organ is not well defined, especially at the genomic level. The objective of this study was therefore to investigate estradiol- and ESR1-dependent regulation of the transcriptome of the oviduct using transgenic mice, both with (ESR1KO) and without (wild-type, WT) a global deletion of ESR1. Oviducts were collected from ESR1KO and WT littermates at 23 days of age, or ESR1KO and WT mice were treated with 5 IU PMSG to stimulate follicular development and the production of ovarian estradiol, and the oviducts collected 48 h later. RNA extracted from whole oviducts was hybridized to Affymetrix Genechip Mouse Genome 430-2.0 arrays (n = 3 arrays per genotype and treatment) or reverse transcribed to cDNA for analysis of the expression of selected mRNAs by real-time PCR. Following microarray analysis, a statistical two-way ANOVA and pairwise comparison (LSD test) revealed 2428 differentially expressed transcripts (DEG's, P < 0.01). Genotype affected the expression of 2215 genes, treatment (PMSG) affected the expression of 465 genes, and genotype x treatment affected the expression of 438 genes. With the goal of determining estradiol/ESR1-regulated function, gene ontology (GO) and bioinformatic pathway analyses were performed on DEG's in the oviducts of PMSG-treated ESR1KO versus PMSG-treated WT mice. Significantly enriched GO molecular function categories included binding and catalytic activity. Significantly enriched GO cellular component categories indicated the extracellular region. Significantly enriched GO biological process categories involved a single organism, modulation of a measurable attribute and developmental processes. Bioinformatic analysis revealed ESR1-regulation of the immune response within the oviduct as the primary canonical pathway. In summary, a transcriptomal profile of estradiol- and ESR1-regulated gene expression and related bioinformatic analysis is presented to increase our understanding of how estradiol/ESR1 affects function of the oviduct, and to identify genes that may be proven as important regulators of fertility in the future.

Dataset Information

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

Publications

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

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