| 1. |
- Andersson, S, et al.
(författare)
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Inactivation of liver X receptor beta leads to adult-onset motor neuron degeneration in male mice
- 2005
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 102:10, s. 3857-3862
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Tidskriftsartikel (refereegranskat)abstract
- Male mice with inactivated liver X receptor (LXR) β suffer from adult-onset motor neuron degeneration. By 7 months of age, motor coordination is impaired, and this condition is associated with lipid accumulation and loss of motor neurons in the spinal cord, together with axonal atrophy and astrogliosis. Several of these features are reminiscent of the neuropathological signs of chronic motor neuron disease such as amyotrophic lateral sclerosis. Because the LXRs are important for cholesterol and lipid metabolism, we speculate that absence of LXRβ leads to pathological accumulation of sterols and lipids that may themselves be neurotoxic or may modulate intracellular pathways and thereby predispose motor neurons to degeneration.
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| 2. |
- Butler, R, et al.
(författare)
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Uric acid stones in the urinary bladder of aryl hydrocarbon receptor (AhR) knockout mice
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 109:4, s. 1122-1126
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Tidskriftsartikel (refereegranskat)abstract
- The aryl hydrocarbon receptor (AhR) knockout mice raised in the laboratory of Fujii-Kuriyama have been under investigation for several years because of the presence in their urinary bladder of large, yellowish stones. The stones are composed of uric acid and become apparent in the bladders as tiny stones when mice are 10 wk of age. By the time the mice are 6 mo of age, there are usually two or three stones with diameters of 3–4 mm. The urate concentration in the serum was normal but in the urine the concentration was 40–50 mg/dL, which is 10 times higher than that in the WT littermates. There were no apparent histological pathologies in the kidney or joints and the levels of enzymes involved in elimination of purines were normal. The source of the uric acid was therefore judged to be from degradation of nucleic acids due to a high turnover of cells in the bladder itself. The bladder was fibrotic and the luminal side of the bladder epithelium was filled with eosinophilic granules. There was loss of E-cadherin between some epithelial cells, with an enlarged submucosal area filled with immune cells and sometimes invading epithelial cells. We hypothesize that in the absence of AhR there is loss of detoxifying enzymes, which leads to accumulation of unconjugated cytotoxins and carcinogens in the bladder. The presence of bladder toxins may have led to the increased apoptosis and inflammation as well as invasion of epithelial cells in the bladders of older mice.
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| 3. |
- Choleris, E, et al.
(författare)
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An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice
- 2003
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 100:10, s. 6192-6197
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens control many physiological and behavioral processes, some of which are connected to reproduction. These include sexual and other social behaviors. Here we implicate four gene products in a micronet required for mammalian social recognition, through which an individual learns to recognize other individuals. Female mice whose genes for the neuropeptide oxytocin (OT) or the estrogen receptor (ER)-β or ER-α had been selectively “knocked out” were deficient specifically in social recognition and social anxiety. There was a remarkable parallelism among results from three separate gene knockouts. The data strongly suggest the involvement in social recognition of the four genes coding for ER-α, ER-β, OT, and the OT receptor. We thus propose here a four-gene micronet, which links hypothalamic and limbic forebrain neurons in the estrogen control over the OT regulation of social recognition. In our model, estrogens act on the OT system at two levels: through ER-β, they regulate the production of OT in the hypothalamic paraventricular nucleus, and through ER-α, they drive the transcription of the OT receptor in the amygdala. The proper operation of a social recognition mechanism allows for the expression of appropriate social behaviors, aggressive or affiliative.
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| 4. |
- DAHLMANWRIGHT, K, et al.
(författare)
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Structural characterization of a minimal functional transactivation domain from the human glucocorticoid receptor
- 1995
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 92:5, s. 1699-1703
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Tidskriftsartikel (refereegranskat)abstract
- A 58-amino acid polypeptide containing the functional core region, the tau 1 core, of the major transactivation domain of the human glucocorticoid receptor has been expressed in Escherichia coli and purified to homogeneity. The polypeptide retains 60-70% of the activity of the intact domain when assayed in vivo or in vitro. This report describes a structural characterization of the tau 1 core peptide fragment. Circular dichroism spectroscopy shows that the tau 1 core and a larger fragment encompassing the intact tau 1 domain are largely unstructured in water solution under a variety of pH conditions. The tau 1 core, however, acquires a significant alpha-helical structure when analyzed in the presence of trifluoroethanol, an agent that favors secondary structure formation in regions that have propensity for alpha-helical conformation. Two- and three-dimensional NMR spectroscopy of 15N-labeled tau 1 core, in the presence of trifluoroethanol, has allowed sequential assignment of 1H and 15N resonances and identification of three protein segments with alpha-helical character. Potentially helix-breaking proline substitutions, in proposed alpha-helical regions, lead to reduced activity, suggesting that alpha-helices are important for transactivation in vivo.
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| 5. |
- Forster, C, et al.
(författare)
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Involvement of estrogen receptor beta in terminal differentiation of mammary gland epithelium
- 2002
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 99:24, s. 15578-15583
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Tidskriftsartikel (refereegranskat)abstract
- The mammary glands of prepubertal estrogen receptor (ER)β−/− mice are morphologically indistinguishable from those of WT littermates. It appears that, although ERβ is expressed in the mouse mammary gland, it is not involved in ductal growth of the gland. In this study, we examined the possibility that ERβ has a role in the differentiated function of the mammary gland. Pregnancy is rare in ERβ−/− mice, but an intensive breeding program produced seven pregnant ERβ−/− mice, of which five did not eat their offspring and continued to successful lactation. Histomorphological comparison of lactating glands revealed that alveoli were larger and there was less secretory epithelium in ERβ−/− than in WT mice. Ultrastructural analysis showed abundant milk droplets and normal apical villi in the luminal epithelial cells, but the extracellular matrix and lamina basalis were reduced, and very frequently the interepithelial cell space was increased. Levels of the adhesion molecules, E-cadherin, connexin 32, occludin, and integrin α2 were reduced, and no zona occludens was detectable. In addition, there was widespread expression of the proliferation marker, Ki-67, in luminal epithelial cells in ERβ−/− but not in WT mice. These findings suggest a role for ERβ in organization and adhesion of epithelial cells and hence for differentiated tissue morphology. We speculate that, because a reduced risk for breast cancer is conferred on women who breast-feed at an early age, ERβ could contribute to this risk reduction by facilitating terminal differentiation of the mammary gland.
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| 6. |
- Garey, J, et al.
(författare)
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Genetic contributions to generalized arousal of brain and behavior
- 2003
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 100:19, s. 11019-11022
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Tidskriftsartikel (refereegranskat)abstract
- We have identified a generalized arousal component in the behavior of mice. Analyzed by mathematical/statistical approaches across experiments, investigators, and mouse populations, it accounts for about 1/3 of the variance in arousal-related measures. Knockout of the gene coding for the classical estrogen receptor (ER-α), a ligand-activated transcription factor, greatly reduced arousal responses. In contrast, disrupting the gene for a likely gene duplication product, ER-β, did not have these effects. A combination of mathematical and genetic approaches to arousal in an experimentally tractable mammal opens up analysis of a CNS function of considerable theoretical and practical significance.
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| 7. |
- Karas, RH, et al.
(författare)
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Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice
- 1999
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 96:26, s. 15133-15136
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Tidskriftsartikel (refereegranskat)abstract
- The protective effects of estrogen in the cardiovascular system result from both systemic effects and direct actions of the hormone on the vasculature. Two estrogen receptors have been identified, ERα and ERβ. We demonstrated previously that estrogen inhibits the response to vascular injury in both wild-type and ERα-deficient mice, and that ERβ is expressed in the blood vessels of each, suggesting a role for ERβ in the vascular protective effects of estrogen. In the present study, we examined the effect of estrogen administration on mouse carotid arterial injury in ERβ-deficient mice. Surprisingly, in ovariectomized female wild-type and ERβ knockout mice, 17β-estradiol markedly and equally inhibited the increase in vascular medial area and the proliferation of vascular smooth muscle cells after vascular injury. These data demonstrate that ERβ is not required for estrogen-mediated inhibition of the response to vascular injury, and suggest that either of the two known estrogen receptors is sufficient to protect against vascular injury, or that another unidentified estrogen receptor mediates the vascular protective effects of estrogen.
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| 8. |
- Krege, JH, et al.
(författare)
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Generation and reproductive phenotypes of mice lacking estrogen receptor beta
- 1998
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 95:26, s. 15677-15682
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ERα and ERβ. We previously generated and studied knockout mice lacking estrogen receptor α and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor β (ERβ −/−) by insertion of a neomycin resistance gene into exon 3 of the coding gene by using homologous recombination in embryonic stem cells. Mice lacking this receptor develop normally and are indistinguishable grossly and histologically as young adults from their littermates. RNA analysis and immunocytochemistry show that tissues from ERβ −/− mice lack normal ERβ RNA and protein. Breeding experiments with young, sexually mature females show that they are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice. Superovulation experiments indicate that this reduction in fertility is the result of reduced ovarian efficiency. The mutant females have normal breast development and lactate normally. Young, sexually mature male mice show no overt abnormalities and reproduce normally. Older mutant males display signs of prostate and bladder hyperplasia. Our results indicate that ERβ is essential for normal ovulation efficiency but is not essential for female or male sexual differentiation, fertility, or lactation. Future experiments are required to determine the role of ERβ in bone and cardiovascular homeostasis.
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| 9. |
- Kudwa, AE, et al.
(författare)
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A previously uncharacterized role for estrogen receptor beta: defeminization of male brain and behavior
- 2005
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 102:12, s. 4608-4612
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Tidskriftsartikel (refereegranskat)abstract
- Sex differences in brain and behavior are ubiquitous in sexually reproducing species. One cause of sexual dimorphisms is developmental differences in circulating concentrations of gonadal steroids. Neonatal testes produce androgens; thus, males are exposed to both testosterone and estradiol, whereas females are not exposed to high concentrations of either hormone until puberty. Classically, the development of neural sex differences is initiated by estradiol, which activates two processes in male neonates; masculinization, the development of male-type behaviors, and defeminization, the loss of the ability to display female-type behaviors. Here, we test the hypothesis that defeminization is regulated by estrogen receptor β (ERβ). Adult male ERβ knockout and WT mice were gonadectomized, treated with female priming hormones, and tested for receptive behavior. Indicative of incomplete defeminization, male ERβ knockout mice showed significantly higher levels of female receptivity as compared with WT littermates. Testes-intact males did not differ in any aspects of their male sexual behavior, regardless of genotype. In olfactory preference tests, males of both genotypes showed equivalent preferences for female-soiled bedding. Based on these results, we hypothesize that ERβ is involved in defeminization of brain and behavior. This aspect of ERβ function may lead to developments in our understanding of neural-based sexually dimorphic human behaviors.
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| 10. |
- Kuiper, GGJM, et al.
(författare)
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Cloning of a novel receptor expressed in rat prostate and ovary
- 1996
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 93:12, s. 5925-5930
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Tidskriftsartikel (refereegranskat)abstract
- We have cloned a novel member of the nuclear receptor superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library and it encodes a protein of 485 amino acid residues with a calculated molecular weight of 54.2 kDa. Clone 29 protein is unique in that it is highly homologous to the rat estrogen receptor (ER) protein, particularly in the DNA-binding domain (95%) and in the C-terminal ligand-binding domain (55%). Expression of clone 29 in rat tissues was investigated by in situ hybridization and prominent expression was found in prostate and ovary. In the prostate clone 29 is expressed in the epithelial cells of the secretory alveoli, whereas in the ovary the granuloma cells in primary, secondary, and mature follicles showed expression of clone 29. Saturation ligand-binding analysis of in vitro synthesized clone 29 protein revealed a single binding component for 17beta-estradiol (E2) with high affinity (Kd= 0.6 nM). In ligand-competition experiments the binding affinity decreased in the order E2 > diethylstilbestrol > estriol > estrone > 5alpha-androstane-3beta,17beta-diol >> testosterone = progesterone = corticosterone = 5alpha-androstane-3alpha,17beta-diol. In cotransfection experiments of Chinese hamster ovary cells with a clone 29 expression vector and an estrogen-regulated reporter gene, maximal stimulation (about 3-fold) of reporter gene activity was found during incubation with 10 nM of E2. Neither progesterone, testosterone, dexamethasone, thyroid hormone, all-trans-retinoic acid, nor 5alpha-androstane-3alpha,I7beta-diol could stimulate reporter gene activity, whereas estrone and 5alpha-androstane-3beta,17beta-diol did. We conclude that clone 29 cDNA encodes a novel rat ER, which we suggest be named rat ERbeta to distinguish it from the previously cloned ER (ERalpha) from rat uterus.
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