Tissue Distribution and Quantitative Analysis of Estrogen Receptor-α (ERα) and Estrogen Receptor-β (ERβ) Messenger Ribonucleic Acid in the Wild-Type and ERα-Knockout Mouse.

Until recently, only a single type of estrogen receptor (ER) was thought to exist and mediate the genomic effects of the hormone 17beta-estradiol in mammalian tissues. However, the cloning of a gene encoding a second type of ER, termed ERbeta, from the mouse, rat, and human has prompted a reevaluation of the estrogen signaling system. Based on in vitro studies, the ERbeta protein binds estradiol with an affinity similar to that of the classical ER (now referred to as ERalpha) and is able to mediate the effects of estradiol in transfected mammalian cell lines. Essential to further investigations of the possible physiological roles of ERbeta, and its possible interactions with ERalpha, are data on the tissue distribution of the two ER types. Herein, we have described the optimization and use of an RNase protection assay able to detect and distinguish messenger RNA (mRNA) transcripts from both the ERalpha and ERbeta genes in the mouse. Because this assay is directly quantitative, a comparison of the levels of expression within various tissues was possible. In addition, the effect of disruption of the ERalpha gene on the expression of the ERbeta gene was also investigated using the ERalpha-knockout (ERKO) mouse. Transcripts encoding ERalpha were detected in all the wild-type tissues assayed from both sexes. In the female reproductive tract, the highest expression of ERbeta mRNA was observed in the ovary and showed great variation among individual animals; detectable levels were observed in the uterus and oviduct, whereas mammary tissue was negative. In the male reproductive tract, significant expression of ERbeta was seen in the prostate and epididymis, whereas the testes were negative. In other tissues of both sexes, the hypothalamus and lung were clearly positive for both ERalpha and ERbeta mRNA. The ERKO mice demonstrated slightly reduced levels of ERbeta mRNA in the ovary, prostate, and epididymis. These data, in combination with the several described phenotypes in both sexes of the ERKO mouse, suggest that the biological functions of the ERbeta protein may be dependent on the presence of ERalpha in certain cell types and tissues. Further characterization of the physiological phenotypes in the ERKO mice may elucidate possible ERbeta specific actions.

[1]  J. Gustafsson,et al.  Mouse estrogen receptor beta forms estrogen response element-binding heterodimers with estrogen receptor alpha. , 1997, Molecular endocrinology.

[2]  K. Korach,et al.  Role of Estrogen Receptor- in the Anterior Pituitary Gland , 1997 .

[3]  K. Korach,et al.  Vascular estrogen receptors and endothelium-derived nitric oxide production in the mouse aorta. Gender difference and effect of estrogen receptor gene disruption. , 1997, The Journal of clinical investigation.

[4]  N. Copeland,et al.  Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. , 1997, Molecular endocrinology.

[5]  D. Pfaff,et al.  Behavioral effects of estrogen receptor gene disruption in male mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Gustafsson,et al.  Estrogen receptor-beta mRNA expression in rat ovary: down-regulation by gonadotropins. , 1997, Molecular endocrinology.

[7]  B. Komm,et al.  The distribution of estrogen receptor-β mRNA in the rat hypothalamus , 1996, Steroids.

[8]  B. Gladen,et al.  Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. , 1996, Endocrinology.

[9]  K. Korach,et al.  Disruption of estrogen receptor gene prevents 17 beta estradiol-induced angiogenesis in transgenic mice. , 1996, Endocrinology.

[10]  J. Polman,et al.  ERβ: Identification and characterization of a novel human estrogen receptor , 1996 .

[11]  D. Pfaff,et al.  Reversal of sex roles in genetic female mice by disruption of estrogen receptor gene. , 1996, Neuroendocrinology.

[12]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[13]  K. Korach,et al.  Disruption of the mouse oestrogen receptor gene: resulting phenotypes and experimental findings. , 1995, Biochemical Society transactions.

[14]  K. Korach,et al.  Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. , 1995, Molecular endocrinology.

[15]  K. Korach.  Insights from the study of animals lacking functional estrogen receptor. , 1994, Science.

[16]  E. Barrett-Connor,et al.  Heart disease in women. , 1994, Fertility and sterility.

[17]  K. Korach,et al.  Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. , 1994, The New England journal of medicine.

[18]  K. Korach,et al.  Aberrant reproductive phenotypes evident in transgenic mice expressing the wild-type mouse estrogen receptor. , 1994, Endocrinology.

[19]  K. Korach,et al.  Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[20]  B. O’Malley,et al.  Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. , 1993, Molecular endocrinology.

[21]  K. Horwitz,et al.  Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors. , 1993, Molecular endocrinology.

[22]  David C. Lee,et al.  TGFα deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice , 1993, Cell.

[23]  D. Edwards,et al.  Mechanisms controlling steroid receptor binding to specific DNA sequences , 1991, Steroids.

[24]  E. Barrett-Connor,et al.  Estrogen and coronary heart disease in women , 1991, JAMA.

[25]  K. Korach,et al.  Estrogen receptors are essential for female sexual receptivity. , 1997, Endocrinology.

[26]  K. Grandien,et al.  Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors a and b , 1997 .

[27]  K. Korach,et al.  Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. , 1996, Recent progress in hormone research.

[28]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.