| 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. |
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| 3. |
- 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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| 4. |
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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- 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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| 9. |
- 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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| 10. |
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