Disease relevance of Esr2

• Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice [1].
• Furthermore, both male and female adult ERbeta(-/-) mice were reluctant to run on a treadmill and tissue hypoxia became very pronounced after exercise [2].
• To establish whether ERbeta-selective ligands represent a viable approach to improve hormone therapy, we investigated whether the estrogenic activities present in an herbal extract, MF101, used to treat hot flashes, are ERbeta selective [3].
• Neuroprotection by a selective estrogen receptor beta agonist in a mouse model of global ischemia [4].
• The data indicate a significant estrogen receptor-mediated neuroprotection in a global cerebral ischemia model involving ERbeta [4].
• Our data suggest that reduced ERbeta signaling might have a role in the pathogenesis of interstitial cystitis, and ERbeta could be a candidate for a target of medical therapy [5].

Psychiatry related information on Esr2

• Therefore, the OT, ER-alpha, and ER-beta genes are necessary, to different degrees, for social discrimination and, thus, for the modulation of social behavior (e.g. aggression, affiliation) [6].
• We speculate that, because a reduced risk for breast cancer is conferred on women who breast-feed at an early age, ERbeta could contribute to this risk reduction by facilitating terminal differentiation of the mammary gland [7].
• We conclude that ERbeta is necessary for neuronal survival and speculate that this gene could have an important influence on the development of degenerative diseases of the central nervous system, such as Alzheimer's disease and Parkinson's disease, as well as those resulting from trauma and stroke in the brain [8].
• These findings indicate that 1) in both sexes estrogenic regulation of running wheel activity is primarily mediated through the ERalpha, not the ERbeta; and 2) hormone/genotype effects are specific to the type of locomotor activity (i.e. home cage running wheel activity and open field activity) measured [9].
• The presence of monkey ERbeta mRNA in brain regions that lack ERalpha should help to clarify the molecular mechanisms by which E acts in the central nervous system to influence hormone secretion, mood disorders, cognition, and neuroprotection [10].

High impact information on Esr2

• This suggests that ERalpha and ERbeta may play different roles in gene regulation [11].
• Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1 [12].
• Our results establish a role for nuclear receptor phosphorylation in the recruitment of SRC-1 and provide a molecular basis for ligand-independent activation by ER beta via the MAPK pathway [12].
• Several neurotransmitter-containing neurons in the rat paraventricular nucleus coexpress ERbeta including; vasopressin, oxytocin, prolactin, and to a lesser extent corticotrophin releasing hormone [13].
• Moreover, the relationship between ERbeta and serotonin may be critical for the regulation of this behavior by estradiol [13].

Chemical compound and disease context of Esr2

• Our results demonstrate that deletion of ER alpha completely abolishes the protective actions of estradiol in all regions of the brain; whereas the ability of estradiol to protect against brain injury is totally preserved in the absence of ER beta [14].
• Primary macrophages from ERalpha- and ERbeta-deficient severe combined immunodeficiency mice [ERalpha knockout (KO) and ERssKO, respectively] were used to delineate the effects and potential mechanisms via which steroid receptors modulate macrophage function [15].
• Therefore, failed activation of ERbeta, resulting from local stromal aromatase deficiency, in conjunction with increased androgen levels, results in increased epithelial cell proliferation and prostatic hyperplasia [16].
• However, alphaERKO mice undergo a 10-fold increase in 17beta-estradiol (E2), and persistent or even increased signaling through ERbeta could be a factor in obesity of alphaERKO mice [17].
• DES induced prostatic squamous metaplasia (SQM) in wt and betaERKO but not in alphaERKO mice, indicating an essential role for ERalpha, but not ERbeta, in the induction of SQM of prostatic epithelium [18].

Biological context of Esr2

• No significant differences in central nervous system histopathology or MBP(Ac1-11)-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype [1].
• However, Esr2(+/-) mice do develop more severe clinical disease with an earlier onset indicating that heterosis at Esr2 plays a significant role in regulating EAE in males [1].
• Immunohistochemical analysis and Western blotting with lung membrane fractions of ERbeta(-/-) mice revealed down-regulation of caveolin-1, increased expression of membrane type-1 metalloproteinase, matrix metalloproteinase 2 (active form), and tissue inhibitors of metalloproteinases 2 [2].
• The percentage of cells in S phase was 1.5% in WT mice and 8% in ERbeta(-/-) mice [19].
• Surprisingly, the coactivator SRC-1 up-regulates mER beta transactivation both in the absence and presence of E2, and in vitro interaction between SRC-1 and the ER beta ligand-binding domain is enhanced by E2 [20].

Anatomical context of Esr2

• The contribution of the hematopoietic and nonhematopoietic cellular compartments associated with the heterotic effect at Esr2 in regulating the severity of clinical EAE was identified using reciprocal hematopoietic radiation bone marrow chimeras generated between male wild-type and Esr2(+/-) mice [1].
• These findings reveal an important role for ERbeta in response to E(2) and in the organization, growth, and differentiation of the uterine epithelium [19].
• In both untreated and E(2)-treated mice, ERalpha and ERbeta were colocalized in the nuclei of many stromal and glandular epithelial cells [19].
• In ERbeta(-/-) mice, there was a marked expression of EGFR in the nuclei of epithelial and stromal cells [19].
• Upon E(2) treatment, EGFR on cell membranes was down-regulated in WT but not in ERbeta(-/-) mice [19].

Associations of Esr2 with chemical compounds

• Sixteen hours after injection of 17beta-estradiol (E(2)), the number of BrdUrd-labeled cells increased 20-fold in WT mice and 80-fold in ERbeta(-/-) mice [19].
• However, upon E(2) + progesterone treatment, ERalpha and ERbeta were not coexpressed in any cells [19].
• Although ERalpha was abundant in intact mice, after ovariectomy, ERalpha could not be detected in the luminal epithelium of either WT or ERbeta(-/-) mice [19].
• Estrogen receptor beta (ER beta) is a novel steroid receptor that is expressed in rat prostate and ovary [20].
• Finally, these data suggest that hypothalamic ERbeta may not be involved in mediating the negative feedback effects of T on serum LH and FSH in male mice [21].

Regulatory relationships of Esr2

• In conclusion, this study demonstrates that endogenously expressed ERbeta is capable of regulating gene transcription independent of ERalpha [22].
• In male urethra, PR was co-expressed with ERbeta in the rhabdosphincter [23].
• Estrogen receptor-beta regulates tryptophan hydroxylase-1 expression in the murine midbrain raphe [24].
• We have previously shown that both ER alpha and ER beta are capable of activating the MAPK pathway in response to a low dose of 17beta-estradiol [25].
• These data demonstrate that both ERalpha and ERbeta are involved in inhibiting LH levels at times of estrogen-negative feedback in vivo [26].

Other interactions of Esr2

• These results highlight the importance of ERalpha for the normal expression of natural reproductive behaviors in both sexes and also provide a background for future studies evaluating ERbeta gene contributions to other, nonreproductive behaviors [27].
• These findings suggest that estrogen induces stromal PR via ERbeta in alphaERKO uterus [28].
• These results suggest that ERbeta is necessary for the regulation of the expression of oxytocin in the PVN [29].
• Oxytocin, but not oxytocin receptor, is rRegulated by oestrogen receptor beta in the female mouse hypothalamus [29].
• A role for the androgen receptor in follicular atresia of estrogen receptor beta knockout mouse ovary [30].

Analytical, diagnostic and therapeutic context of Esr2

• Mouse ER beta bind to an inverted repeat spaced by three nucleotides in a gel mobility shift assay and transactivates promoters containing synthetic or natural estrogen response elements in an estradiol (E2)-dependent manner [20].
• Gonadectomized adult male and female mice were killed, and brains were processed for immunocytochemistry for ERalpha and ERbeta [31].
• The purpose of the present study was to utilize in situ hybridization histochemistry to determine the anatomical distribution of ER beta mRNA in ER alphaKO mouse forebrain [32].
• The present study used in vivo autoradiography to evaluate the binding of 125I-estrogen, a compound with a similar affinity for both ERs to ascertain whether ER beta mRNA is translated into biologically active receptor [33].
• Gene-targeting techniques were used to generate mice lacking either functional ERalpha (alphaERKO), ERbeta (betaERKO), or both ERs (alphabetaERKO) to provide a model for evaluating estrogen receptor action [34].

References