Reversal of Sex Roles in Genetic Female Mice by Disruption of Estrogen Receptor Gene

Ogawa, Sonoko; Taylor, Julia A.; Lubahn, Dennis B.; Korach, Kenneth S.; Pfaff, Donald W.

doi:10.1159/000127154

Cited by 140 publications

(79 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This pattern of findings in ERKO males is more complex than with ERKO females, who simply never show lordosis behavior (23). Surprisingly, ER gene expression appears to be necessary for full expression of both female and male sex behavior repertoires.…”

Section: Discussionmentioning

confidence: 88%

Behavioral effects of estrogen receptor gene disruption in male mice

Ogawa

Lubahn

Korach

et al. 1997

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

Self Cite

464

285

View full text Add to dashboard Cite

Gonadal steroid hormones regulate sexually dimorphic development of brain functions and behaviors. Their nuclear receptors offer the opportunity to relate molecular events in neurons to simple instinctive mammalian behaviors. We have determined the role of estrogen receptor (ER) activation by endogenous estrogen in the development of male-typical behaviors by the use of transgenic estrogenreceptor-deficient (ERKO) mice. Surprisingly, in spite of the fact that they are infertile, ERKO mice showed normal motivation to mount females but they achieved less intromissions and virtually no ejaculations. Aggressive behaviors were dramatically reduced and male-typical offensive attacks were rarely displayed by ERKO males. Moreover, ER gene disruption demasculinized open-field behaviors. In the brain, despite the evident loss of functional ER protein, the androgendependent system appears to be normally present in ERKO mice. Together, these findings indicate that ER gene expression during development plays a major role in the organization of male-typical aggressive and emotional behaviors in addition to simple sexual behaviors.It is well established that gonadal steroid hormones, by acting on the central nervous system, regulate various neuroendocrine events related to reproduction and reproductive behaviors in both sexes. In males, testosterone is a major hormone that facilitates both sexual and aggressive behaviors. The mechanisms underlying the behavioral effects of testosterone, however, are complicated by the fact that endogenous testosterone can act not only through the androgen receptor (AR) as can testosterone metabolite (5␣-reduced dihydrotestosterone), but also can act through estrogen receptors (ER) after being aromatized to estradiol in the target tissues including the brain. The relative importance of AR and ER in the facilitation of male sexual behaviors by testosterone has been studied (1, 2), but a clear role for ER gene expression needs to be determined.Aggressive behaviors in male mice can be regulated in adulthood by both AR-and ER-dependent mechanisms depending on the genotype of the animals (3). Some evidence for the involvement of estrogen-dependent mechanisms in male aggressive behaviors has been obtained by comparing relative efficiencies of testosterone, dihydrotestosterone, and estrogen (4, 5) and by concurrent injection of an aromatase inhibitor with testosterone (6, 7). These findings, however, do not provide direct evidence for the role of the ER gene product itself. Furthermore, the antiestrogen tamoxifen gave inconsistent behavioral effects; both inhibitory (8) and facilitatory (9) effects on aggression in male mice have been reported. Until recently, there was never a direct way to manipulate endogenous steroid receptor function to determine the behavioral role of ER.This became possible through the development of ERdeficient mutant mice (ERKO) by the use of homologous recombination techniques (10-12) .Using ERKO mice, we have assessed more directly the role of ER gene-dependent brai...

show abstract

Section: Discussionmentioning

confidence: 88%

Behavioral effects of estrogen receptor gene disruption in male mice

Ogawa

Lubahn

Korach

et al. 1997

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

Self Cite

464

285

View full text Add to dashboard Cite

show abstract

“…ERa has been localized to the hypothalamus, an important brain region for sexual receptivity. E 2 -facilitated receptivity of rats is blocked by antisense oligonucleotides for ERa (not ERb), and does not occur in ERb (but does occur in ERa) knockout mice (Apostolakis et al, 2000;Ogawa et al, 1996Ogawa et al, , 1998Ogawa et al, , 1999. Further, ERa knockout mice are anovulatory, have dis- The mean (7SEM) number of punished licks made in the Vogel task of ovx rats coadministered vehicle (solid bars) or tamoxifen (striped bars) and vehicle, 17b-E 2 , COUM, or DPN 48 h before testing (n ¼ 7-10/condition).…”

Section: Discussionmentioning

confidence: 99%

ERβ-Selective Estrogen Receptor Modulators Produce Antianxiety Behavior when Administered Systemically to Ovariectomized Rats

Walf

Frye

2005

Neuropsychopharmacol

207

150

View full text Add to dashboard Cite

17b-Estradiol (E 2 ) may influence anxiety behavior; however, its effects and mechanisms are not well understood. To determine whether E 2 's effects on anxiety behavior may involve actions at intracellular estrogen receptor (ER) a or b isoforms, selective ER modulators (SERMs) were administered (10 mg; s.c.) to ovariectomized rats 48 h before testing for anxiety behavior. Rats received sesame oil vehicle, 17b-E 2 , which has a high affinity for ERa and ERb, or SERMs that vary in their activity at ERa and b. ERa-selective SERMs were propyl pyrazole triol (PPT), which has more selective effects at ERa, than does the other ERa SERM utilized, 17a-E 2, which also binds ERb. ERbselective SERMs were diarylpropionitrile (DPN) and 7,12-dihydrocoumestan (coumestrol). DPN is more selective at ERb than coumestrol, which also binds ERa. 17b-E 2 and ERb-selective SERMs (DPN, coumestrol) produced clear antianxiety behavior in the open field, elevated plus maze, emergence, light-dark transition, defensive freezing, and Vogel punished drinking tasks. Anxiety behavior of rats administered ERa-selective SERMs (PPT, 17a-E 2 ) was not different from vehicle; however, PPT and 17a-E 2 enhanced sexual receptivity in a manner similar to 17b-E 2. Coadministration of tamoxifen (10 mg/kg) blocked the antianxiety behavior produced by 17b-E 2 , DPN, or coumestrol. Together, these data suggest that actions at ERb may underlie some of E 2 's antianxiety effects.

show abstract

“…These data suggest the importance of ER-α, but not ER-β, in reproductive functions regulated by estrogen, which supports the results of other studies showing the role of ERs in reproductive function using ER-knockout mice. ER-α knockout male and female mice showed various abnormalities in reproductive aspects, including infertility, no sign of lordosis, and infanticide (Lubahn et al, 1993;Ogawa et al, 1996;Ogawa et al, 1998;Simpson, 1998;Rissman et al, 1999). In contrast, the analyses of reproductive behaviors of ER-β knockout mice indicated the possibility that ER-β is not essential for such behaviors (Krege et al, 1998), since ER-β knockout male and female mice exhibited normal reproductive behaviors (Krege et al, 1998;Ogawa et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Age-related changes in the expression of ER-β mRNA in the female rat brain

Yamaguchi

Yuri

2007

Brain Research

View full text Add to dashboard Cite

Estrogen is important for numerous physiological actions, most of which are mediated via the nuclear estrogen receptors (ERs), ER-α and ER-β, which modulate the transcription of target genes following estrogen binding. Estrogen functions change with age. In the present study, to reveal the effects of normal aging on ER-β expression in the brain, we examined ER-β expression at the transcriptional level using young (10 weeks), middle-aged (12 months) and old (24 months) intact female rats. In situ hybridization using a digoxigenin-labeled RNA probe was used to assess the number of ER-β mRNA-positive cells in each region in whole brain. ER-β mRNA-positive cells were detected throughout the brain in young female rats and were reduced in number in the olfactory bulb, cerebral cortex, hippocampus, accumbens nucleus, part of the amygdala and raphe nucleus of middle-aged rats, but did not decline further in number in aged animals. By contrast, the number of ER-β mRNA-positive cells was decreased in the hippocampus, caudate putamen, claustrum, accumbens nucleus, substantia nigra and cerebellum was not significantly different between young and middle-aged rats, but was decreased in old rats. These results indicate that the expression of ER-β mRNA in the female rat brain is differentially modulated during aging and that the changes are region specific.Section: 2) Nervous System Development, Regeneration and Aging

show abstract

Reversal of Sex Roles in Genetic Female Mice by Disruption of Estrogen Receptor Gene

Cited by 140 publications

References 8 publications

Behavioral effects of estrogen receptor gene disruption in male mice

Behavioral effects of estrogen receptor gene disruption in male mice

ERβ-Selective Estrogen Receptor Modulators Produce Antianxiety Behavior when Administered Systemically to Ovariectomized Rats

Age-related changes in the expression of ER-β mRNA in the female rat brain

Contact Info

Product

Resources

About