Responses in the brain of estrogen receptor α-disrupted mice

Shughrue, Paul J.; Lubahn, Dennis B.; Negro‐Vilar, A.; Korach, Kenneth S.; Merchenthaler, Istvån

doi:10.1073/pnas.94.20.11008

Cited by 92 publications

(49 citation statements)

References 26 publications

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“…However, it is unknown whether non-classical mechanisms additionally play a role in reproductive behavior. ERαKO females do not display lordosis, reject male mice, and display reduced up-regulation of PR by E 2 in the hypothalamus (Kudwa and Rissman, 2003;Shughrue et al, 1997). Preliminary studies from our laboratory have indicated that while ERα −/AA females are unreceptive to males and do not show lordosis behavior, they do display significantly less rejective behavior (e.g.…”

Section: Female Sexual Behaviormentioning

confidence: 92%

New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice

McDevitt

Glidewell-Kenney

Jimenez

et al. 2008

Molecular and Cellular Endocrinology

123

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Estrogen receptor alpha (ERα) mediates estrogen (E 2 ) actions in the brain and is critical for normal reproductive function and behavior. In the classical pathway, ERα binds to estrogen response elements (EREs) to regulate gene transcription. ERα can also participate in several non-classical pathways, including ERE-independent gene transcription via protein-protein interactions with transcription factors and rapid, non-genotropic pathways. To distinguish between ERE-dependent and ERE-independent mechanisms of E 2 action in vivo, we have created ERα null mice that possess an ER knock-in mutation (E207A/G208A; "AA"), in which the mutant ERα cannot bind to DNA but retains activity in ERE-independent pathways (ERα −/AA mice). Understanding the molecular mechanisms of ERα action will be helpful in developing pharmacological therapies that differentiate between ERE-dependent and -independent processes. This review focuses on how the ERα −/AA model has contributed to our knowledge of ERα signaling mechanisms in estrogen regulation of the reproductive axis and sexual behavior. Keywordsestrogen receptor alpha; estrogen response element; non-classical signaling; negative feedback; sexual behaviorThe biological effects of estrogens are mediated through at least two distinct nuclear receptors, ERα and ERβ, which belong to the nuclear hormone receptor superfamily (Mangelsdorf et al., 1995). In the classical pathway of estrogen action, E 2 binds to ER, inducing conformational changes within the receptor that promote dimerization and interaction with coactivator and corepressor molecules. The ligand-receptor complex binds with high affinity to specific estrogen response elements (EREs) in the regulatory regions of target genes to either activate or repress gene expression (Glass, 1994;McKenna et al

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Section: Female Sexual Behaviormentioning

confidence: 92%

New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice

McDevitt

Glidewell-Kenney

Jimenez

et al. 2008

Molecular and Cellular Endocrinology

123

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“…ER␣ mRNA expression is absent in only two ovarian cancer cell cultures (OVCA433 and OVCA420), whereas ER␤ messages are present in all cancer cell cultures/lines at levels comparable to those found in HOSE cells. A lack of PR expression in ER␣/ER␤-positive ovarian cancer cells may represent a state of estrogen resistance because, in most other estrogen-target tissues, PR expression is tightly associated with ER␣ (23,24) or ER␤ (28,29) expression. The notion that ovarian cancer cells are estrogenresistant is supported by clinical observations that tamoxifen treatment is a not an effective therapy for OCs and only 36% of OC specimens coexpress both ER␣ and PR (1)(2)(3)(4).…”

Section: Fig 2 Sequence Analyses Of the Wild-type Er␣ Transcript (Ementioning

confidence: 99%

Expression of human estrogen receptor-α and -β, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells

Lau

Mok

1999

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

256

161

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Our understanding of the roles played by sex hormones in ovarian carcinogenesis has been limited by a lack of data concerning the mode of sex hormone action in human ovarian surface epithelial (HOSE) cells, the tissue of origin of >90% of ovarian cancers. We have compared the relative abundance of estrogen receptor (ER)␣, ER␤, progesterone receptor (PR), and androgen receptor (AR) mRNA in four primary cultures of HOSE cells obtained from postmenopausal women to those found in late serous adenocarcinoma primary cell cultures and established ovarian cancer cell lines. We observed coexpression of ER␣ and ER␤ mRNA along with AR and PR transcripts in normal HOSE cells and disruption of ER␣ mRNA expression as well as dramatic down-regulation of PR and AR transcript expression in most ovarian cancer cells. In contrast, levels of ER␤ mRNA were unaffected by the malignant state. Additionally, a novel mutation involving a 32-bp deletion in exon 1 of ER␣ transcripts was detected in the SKOV3 cell line. This mutation would explain why SKOV3 was reported to be ER-positive but estrogen-insensitive. Taken together, these findings suggest that estrogens, signaling via either or both ER subtypes, may play an indispensable role in regulating normal HOSE cell functions. Therefore, loss of ER␣, PR, and AR mRNA expression in HOSE cells may be responsible for neoplastic transformation in this cell type. In contrast, the roles played by ER␤ in normal and malignant HOSE cells remain elusive. Finally, the coexistence of mutated ER␣ mRNA and normal ER␤ transcripts in SKOV3 argues in favor of a dependency of ER␤ action on functional ER␣s.

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“…7 Although the number of labeled cells and intensity of nuclear concentration of the 125 I-estrogen was attenuated in the ERKO mouse brain when compared with wild-type littermates, these initial studies revealed the presence of a nuclear binding site in the ER disrupted mouse brain. 7 Previous studies from our laboratory have shown that the expression of progesterone receptor (PR) mRNA in the rat preoptic area was markedly enhanced by a small dose of 17␤-estradiol. 8 Since residual estrogen binding was detected in the ERKO preoptic area 7…”

mentioning

confidence: 99%

“…7 The estrogenbinding cells were seen in a number of brain regions including the medial preoptic area (Figure 1a), arcuate nucleus, bed nucleus of the stria terminalis and amygdala. 7 Although the number of labeled cells and intensity of nuclear concentration of the 125 I-estrogen was attenuated in the ERKO mouse brain when compared with wild-type littermates, these initial studies revealed the presence of a nuclear binding site in the ER disrupted mouse brain. 7 Previous studies from our laboratory have shown that the expression of progesterone receptor (PR) mRNA in the rat preoptic area was markedly enhanced by a small dose of 17␤-estradiol.…”

mentioning

confidence: 99%

“…Evaluation of brain sections revealed cells in the ERKO mouse brain capable of concentrating 125 I-estrogen. 7 The estrogenbinding cells were seen in a number of brain regions including the medial preoptic area (Figure 1a), arcuate nucleus, bed nucleus of the stria terminalis and amygdala. 7 Although the number of labeled cells and intensity of nuclear concentration of the 125 I-estrogen was attenuated in the ERKO mouse brain when compared with wild-type littermates, these initial studies revealed the presence of a nuclear binding site in the ER disrupted mouse brain.…”

mentioning

confidence: 99%

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Estrogen action in the estrogen receptor α-knockout mouse: is this due to ER-β?

Shughrue¹

1998

Mol Psychiatry

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In vivo autoradiographic studies have shown that neurons in the estrogen receptor-␣ knockout (ERKO) mouse brain are capable of concentrating radiolabeled estrogen. In one region of the ERKO hypothalamus that binds estrogen, the preoptic area, we have also shown that a variety of estrogenic compounds modulate the expression of progesterone receptor. Recently, a second estrogen receptor (ER-␤) was isolated from the rat prostate. In situ hybridization studies have demonstrated that ER-␤ mRNA is present in the rat brain as well as the preoptic area of the ERKO mouse brain. Interestingly, ER-␤ mRNA was also detected in regions of the brain where the classical ER is sparse or absent, including the cerebral cortex and hippocampus. Together, the results of these studies suggest the presence and functionality of a nonclassical estrogen receptor in the ERKO brain and provided evidence that this receptor may be ER-␤. Moreover, the localization of ER-␤ mRNA in many new brain regions, including those associated with learning and memory, may provide new insight about the anatomical substrate for estrogen action in the brain.Keywords: ERKO; rat; steroid; cortex; hippocampus Estrogen has a profound effect on the developing and adult mammalian brain. In the developing brain, estrogen action has been shown to promote neuronal differentiation and is thought to establish a sex dimorphism in the 'wiring' of certain neuronal pathways. The differential action of estrogen on the brain determines the phenotype of adult brain function, including the pattern of gonadotropin release, proceptive and receptive behavior and other aspects of procreation. It is generally accepted that estrogen regulates these physiological events by binding to its nuclear estrogen receptor (ER), interacting with a specific DNA response element and thereby modulating the expression of certain genes. Through the use of a variety of histochemical techniques, 1-4 ER has been detected in anatomically distinct regions of the brain, areas where estrogen has been shown to modulate events essential for procreation. Studies with a transgenic mouse which lacks a functional ER have verified the importance of ER in procreation, since ER knockout (ERKO) mice are infertile, probably due to deficits in reproductive behavior and an abnormal estrous cycle. 5 observations), suggested that some genes that are regulated by estrogen in the wild-type animal were still sensitive to changes in estrogen in the ERKO mouse brain.In order to characterize the residual estrogen activity seen in the ERKO mouse brain, we used high resolution steroid autoradiography 6 with an iodinated estrogen ( 125 I-estrogen) to assess the presence and distribution of estrogen-binding sites. This technique was selected because it allowed us to detect any estrogenbinding site, including ER, splicing variants of ER or unknown estrogen receptors, while techniques such as in situ hybridization and immunocytochemistry were limited to evaluating known mRNAs or proteins. In these studies, ERKO and wild-type mice w...

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Responses in the brain of estrogen receptor α-disrupted mice

Cited by 92 publications

References 26 publications

New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice

New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice

Expression of human estrogen receptor-α and -β, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells

Estrogen action in the estrogen receptor α-knockout mouse: is this due to ER-β?

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