Engineering of a Mouse for the in Vivo Profiling of Estrogen Receptor Activity

Ciana, Paolo

doi:10.1210/me.15.7.1104

Cited by 97 publications

(100 citation statements)

References 23 publications

(28 reference statements)

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“…In the plasma of pregnant mice exposed to 14 C-DES, a rapid disappearance of DES was found with a subsequent peak of DES conjugates after 8 h (McLachlan 1977), consistent with the peak we observed in luciferase activity in the transgenic mice. Exposure of the transgenic mice to E 2 resulted in a luciferase activity peak after 8 h. Similarly, target gene activity in transgenic pMAR mice peaked in liver and bone 6 h after E 2 exposure (Ciana et al 2001(Ciana et al , 2003. With respect to EP, its transactivation activity was highest 24 h after exposure, as shown with the IVIS system.…”

Section: Figurementioning

confidence: 80%

“…Organs showing a high fold induction of luciferase after estrogen exposure include bone, adrenal, liver, prostate, kidney, colon and lung. Some of these organs were also found to be relatively responsive in pMAR mice, although the fold induction was lower than in INS7 mice (Ciana et al 2001, Di Lorenzo et al 2002, while adrenal and colon tissue was not described. In ERIN mice, high inducibility was found in the kidney and slight induction in the adrenal gland, but no induction was found in lung, while bone, prostate and colon were not examined (Nagel et al 2001).…”

Section: Figurementioning

confidence: 88%

“…In addition, to improve expression and minimize effects of DNA sequences surrounding the transgene, transgenic mice carrying a similar construct flanked by two copies of the chick -globin insulator (Chung et al 1993, Wang et al 1997, Potts et al 2000 were generated. Although other estrogen reporter mice have been generated, these models do not exclude EREindependent activation because of the presence of other promoter sequences (Ciana et al 2001, Nagel et al 2001, Toda et al 2003. The use of only a minimal TATA-box in the construct used in the present study will avoid activation of the construct via other promoter sites than the EREs.…”

Section: Introductionmentioning

confidence: 99%

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Tissue- and time-dependent estrogen receptor activation in estrogen reporter mice

Lemmen¹,

Arends²,

Boxtel³

et al. 2004

Journal of Molecular Endocrinology

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With the aim of developing an in vivo model that directly detects activation of estrogen receptors (ERs), transgenic mice carrying a luciferase reporter gene were generated. The luciferase reporter gene was under the control of three consensus estrogen-responsive elements (EREs) coupled to a minimal TATA-box, with or without flanking chick -globin insulators. By using this model in combination with the IVIS imaging system, in vivo ER activation was measured. Dose-and time-dependent luciferase activity was induced in various organs of adult transgenic male mice exposed to diethylstilbestrol (DES) (10-1000 µg/kg) and 17 -estradiol dipropionate (EP) (10-1000 µg/kg), when luciferase activity was measured ex vivo. The highest (>10 000-fold) induction of luciferase was measured in bone and kidney 24 h after exposure to 1000 µg/kg EP. Other highly responsive organs include liver, testis, pituitary, brain, prostate and colon, which show different activity profiles. This in vivo model for detecting estrogenic activity can be used to assess tissue-specific action of ER agonists and antagonists. These could include selective ER modulators and environmental estrogens. In combination with the IVIS imaging system, this in vivo model is a powerful tool for assessing the kinetics of gene activation by estrogenic compounds.

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Section: Figurementioning

confidence: 80%

Section: Figurementioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tissue- and time-dependent estrogen receptor activation in estrogen reporter mice

Lemmen¹,

Arends²,

Boxtel³

et al. 2004

Journal of Molecular Endocrinology

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“…The oestrogen-ER complex can also interact with other transcription factors, such as Ap1, Sp1 and Nfkb (listed as Nfkb in the MGI Database), and initiate transcription without binding directly to DNA via the non-classical pathways (Galien & Garcia 1997, Kushner et al 2000. Oestrogens have been demonstrated to affect gene transcription in oestrogen-responsive organs, such as bone and uterus, via both classical and non-classical signalling pathways (Ciana et al 2001, Jakacka et al 2002, Syed et al 2005, Windahl et al 2007.…”

Section: Introductionmentioning

confidence: 99%

In vivo activation of gene transcription via oestrogen response elements by a raloxifene analogue

Engdahl

Jochéms

Gustafsson

et al. 2009

Journal of Endocrinology

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Raloxifene is a selective oestrogen receptor modulator with tissue-specific effects. The mechanisms behind the effects of raloxifene are partly unclear, and the aim of the present study was to investigate whether raloxifene can activate the classical oestrogen-signalling pathway in vivo in three known oestrogen-responsive organs, uterus (reproductive organ), bone (non-reproductive organ) and thymus (immune organ). For this purpose, we have used reporter mice with a luciferase gene under control of oestrogen-responsive elements (EREs), enabling detection of in vivo activation of gene transcription via the classical oestrogen pathway. Three-month-old ovariectomized ERE-luciferase mice were treated with the raloxifene analogue (LY117018), oestradiol (OE 2 ) or vehicle for 3 weeks. Luciferase activation was measured in bone, uterus and thymus, and compared to bone parameters, and uterus and thymus weights. The raloxifene analogue affected bone mineral density (BMD) to the same extent as OE 2 , and both treatments resulted in increased luciferase activity in bone. As expected, OE 2 treatment resulted in increased uterus weight and increased uterine luciferase activity, while the effect of LY117018 on uterus weight and luciferase activity was modest and significantly lower than the effect of OE 2 . LY117018 and OE 2 treatment resulted in similar luciferase activation in thymus. However, only OE 2 treatment resulted in thymic atrophy, while no effect on thymus weight was seen after LY117018 treatment. In summary, the raloxifene analogue LY117018 can activate the classical oestrogen pathway in bone, uterus and thymus in vivo, and this activation is associated with BMD and uterus weight, but not thymus weight.

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“…Application of the ER responsive element (ERE)-Luc reporter mouse, a transgenic mouse in which the luciferase reporter is driven by a promoter carrying multiple ERE copies (6), identified the liver as the organ in which ERs are most transcriptionally active (7,8). Further studies demonstrated that hepatic ERα transcriptional activity oscillates with the estrous cycle (tetradian oscillation) and is regulated by several compounds, including growth factors and nutritional proteins (9).…”

mentioning

confidence: 99%

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

Villa

Torre²,

Stell³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

117

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In the liver of female mice, the transcriptional activity of estrogen receptor (ER) α oscillates in phase with the 4-d-long estrous cycle. Here systemic, genome-wide analysis demonstrates that ER tetradian oscillation is necessary to generate pulses of expression in genes for fatty acid and cholesterol synthesis. This ER-dependent metabolic programming changes with pregnancy and after cessation of ovarian function due to age or surgical menopause, suggesting that ER signaling is optimized to coordinate liver functions with the energetic requirements of each reproductive stage. Alterations of amplitude and frequency of the tetradian cycle, as observed after surgical menopause, age, or specific ablation of the hepatic Igf-1 gene, are associated with liver fat deposition. Appropriate hormone replacement therapy reinstating the oscillatory activity of liver ER prevents the effect of surgical menopause on fat deposition in liver.energy metabolism | estrogen action | steroid hormone physiology | selective estrogen receptor modulators E strogen receptor (ER) α (or ESR1 or NR3A) is a transcription factor regulated by estrogens and nonestrogenic substances. ERα is highly expressed in reproductive organs and is indispensable for female reproductive functions (1). ERα is also present in most nonreproductive organs, where its role is currently object of intense investigation because of the large number of dysfunctions associated with the postmenopause and affecting the metabolic, cardiovascular, and immune systems (2-5).Application of the ER responsive element (ERE)-Luc reporter mouse, a transgenic mouse in which the luciferase reporter is driven by a promoter carrying multiple ERE copies (6), identified the liver as the organ in which ERs are most transcriptionally active (7,8). Further studies demonstrated that hepatic ERα transcriptional activity oscillates with the estrous cycle (tetradian oscillation) and is regulated by several compounds, including growth factors and nutritional proteins (9). This latter mechanism is instrumental for the synthesis of the circulating insulin-like growth factor 1 (IGF-1) necessary for the progression of the estrous cycle (9).These studies pointed to the hepatic ERα as a sensor of nutrient availability and a switch able to block the reproductive cycle in the event of malnutrition. On the other hand, a large body of evidence indicates that ERs are important regulators of several aspects of liver energy metabolism. Phenotypic analysis of mutant mice, including ERα (ERKO), ERβ, and aromatase KO mice, demonstrated that ERs play a pivotal role in the regulation of many processes related to the control of energy homeostasis, including energy expenditure, insulin sensitivity, and fat distribution (1, 10-13). In addition, investigation of the genetic programs controlled by hepatic ERs performed by comparing the transcriptomes of vehicle-and 17β-estradiol (E 2 )-treated ovariectomized (ovx) mice (14) established the potential for ER to recognize and regulate the transcription of numerous genes in...

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Engineering of a Mouse for the in Vivo Profiling of Estrogen Receptor Activity

Cited by 97 publications

References 23 publications

Tissue- and time-dependent estrogen receptor activation in estrogen reporter mice

Tissue- and time-dependent estrogen receptor activation in estrogen reporter mice

In vivo activation of gene transcription via oestrogen response elements by a raloxifene analogue

Tetradian oscillation of estrogen receptor α is necessary to prevent liver lipid deposition

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