Estrogen receptor 2b is the major determinant of sex-typical mating behavior and sexual preference in medaka

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Proximate perspectives on the evolution of female aggression: good for the gander,good for the goose?

Female–female aggression often functions in competition over reproductive or social benefits, but the proximate mechanisms of this apparently adaptive behaviour are not well understood. The sex steroid hormone testosterone (T) and its metabolites are well-established mediators of male–male aggression, and several lines of evidence suggest that T-mediated mechanisms may apply to females as well. However, a key question is whether mechanisms of female aggression primarily reflect correlated evolutionary responses to selection acting on males, or whether direct selection acting on females has made modifications to these mechanisms that are adaptive in light of female life history. Here, I examine the degree to which female aggression is mediated at the level of T production, target tissue sensitivity to T, or downstream genomic responses in order to test the hypothesis that selection favours mechanisms that facilitate female aggression while minimizing the costs of systemically elevated T. I draw heavily from avian systems, including the dark-eyed junco (Junco hyemalis), as well as other organisms in which these mechanisms have been well studied from an evolutionary/ecological perspective in both sexes. Findings reveal that the sexes share many behavioural and hormonal mechanisms, though several patterns also suggest sex-specific adaptation. I argue that greater attention to multiple levels of analysis—from hormone to receptor to gene network, including analyses of individual variation that represents the raw material of evolutionary change—will be a fruitful path for understanding mechanisms of behavioural regulation and intersexual coevolution.     

Neural sensitivity to sex steroids predicts individual differences in aggression: implications for behavioural evolution

Testosterone (T) regulates many traits related to fitness, including aggression. However, individual variation in aggressiveness does not always relate to circulating T, suggesting that behavioural variation may be more closely related to neural sensitivity to steroids, though this issue remains unresolved. To assess the relative importance of circulating T and neural steroid sensitivity in predicting behaviour, we measured aggressiveness during staged intrusions in free-living male and female dark-eyed juncos (Junco hyemalis). We compared aggressiveness to plasma T levels and to the abundance of androgen receptor (AR), aromatase (AROM) and oestrogen receptor alpha (ORα) mRNA in behaviourally relevant brain areas (avian medial amygdala, hypothalamus and song control regions). We also asked whether patterns of covariation among behaviour and endocrine parameters differed in males and females, anticipating that circulating T may be a better predictor of behaviour in males than in females. We found that circulating T related to aggressiveness only in males, but that gene expression for ORα, AR and AROM covaried with individual differences in aggressiveness in both sexes. These findings are among the first to show that individual variation in neural gene expression for three major sex steroid-processing molecules predicts individual variation in aggressiveness in both sexes in nature. The results have broad implications for our understanding of the mechanisms by which aggressive behaviour may evolve.     

Genotype/age interactions on aggressive behavior in gonadally intact estrogen receptor beta knockout (betaERKO) male mice

Estrogen, as an aromatized metabolite of testosterone, has a facilitatory effect on male aggressive behavior in mice. Two subtypes of estrogen receptors, alpha (ER-alpha) and beta (ER-beta), in the brain are known to bind estrogen. Previous studies revealed that the lack of ER-alpha gene severely reduced the induction of male aggressive behavior. In contrast, mice that lacked the ER-beta gene tended to be more aggressive than wild type (WT) control mice, although the behavioral effects of ER-beta gene disruption were dependent on their social experience. These findings lead us to hypothesize that estrogen may facilitate aggression via ER-alpha whereas it may inhibit aggression via ER-beta. In the present study, we further investigated the role of ER-beta in the regulation of aggressive behavior by examining developmental changes starting at the time of first onset, around the age of puberty. Aggressive behaviors of ER-beta gene knockout (betaERKO) mice were examined in three different age groups, puberty, young-adult, and adult. Each mouse was tested every other day for three times in a resident-intruder paradigm against olfactory bulbectomized intruder mice and their trunk blood was collected for measurements of serum testosterone after the completion of the study. Overall, betaERKO mice were significantly more aggressive than WT. These genotype differences were more pronounced in puberty and young adult age groups, but not apparent in the adult age group, in which betaERKO mice were less aggressive than those in two younger age groups. Serum testosterone levels of betaERKO mice were significantly higher than those of WT mice only in the pubertal age group, but not in young adult (when betaERKO mice were still significantly more aggressive than WT mice) and adult (when no genotype differences in aggression were found) age groups. These results suggest that ER-beta mediated actions of gonadal steroids may more profoundly be involved in the inhibitory regulation of aggressive behavior in pubertal and young adult mice.     

雄激素和雌激素受体药物筛选方法的研究进展

雄激素和雌激素受体通过与相应激素特异性结合促进细胞分化和组织生长,发挥重要的生理功能,其功能失调可诱发多种疾病。雄激素和雌激素受体的选择性调节剂是治疗相关疾病的重要药物。基于基因组学、分子生物学、细胞生物学和生物信息学等最新研究成果而发展形成的实验技术或方法被用于新型雄激素和雌激素受体调节剂的筛选,显著加快了新药开发的进程。     

DAX-1, as an androgen-target gene,inhibits aromatase expression: a novel mechanism blocking estrogen-dependent breast cancer cell proliferation

Sexual hormones, estrogens and androgens, determine biological response in a tissue- and gender-specific manner and have a pivotal role in endocrine-mediated tumorigenesis. In situ estrogen production by aromatase is a critical determinant for breast cancer growth and progression. On the contrary, clinical and in vitro studies indicate that androgens have a protective role in mammary carcinogenesis. Here, we demonstrated, in hormone-dependent breast cancer cells, the existence of a functional interplay between the androgen receptor (AR), the orphan nuclear receptor DAX-1 and the aromatase enzyme involved in the inhibition of the estrogen-dependent breast cancer cell proliferation exerted by androgen signaling. Indeed, our results revealed, in MCF-7 cells, that ligand-activated AR induces the expression of the orphan nuclear receptor DAX-1 by direct binding to a newly identified androgen-response-element within the DAX-1 proximal promoter. In turn, androgen-induced DAX-1 is recruited, in association with the corepressor N-CoR, within the SF-1/LRH-1 containing region of the aromatase promoter, thereby repressing aromatase expression and activity. In elucidating a novel mechanism by which androgens, through DAX-1, inhibit aromatase expression in breast cancer cell lines, these findings reinforce the theory of androgen- opposing estrogen-action, opening new avenues for therapeutic intervention in estrogen-dependent breast tumors.     

Parallel evolution between aromatase and androgen receptor in the animal kingdom

There are now many known cases of orthologous or unrelated proteinsin different species that have undergone parallel evolutionto satisfy a similar function. However, there are no reportedcases of parallel evolution for proteins that bind a commonligand but have different functions. We focused on two proteinsthat have different functions in steroid hormone biosynthesisand action but bind a common ligand, androgen. The first protein,androgen receptor (AR), is a nuclear hormone receptor and thesecond one, aromatase (cytochrome P450 19 [CYP19]), convertsandrogen to estrogen. We hypothesized that binding of the androgenligand has exerted common selective pressure on both AR andCYP19, resulting in a signature of parallel evolution betweenthese two proteins, though they perform different functions.Consistent with this hypothesis, we found that rates of aminoacid change in AR and CYP19 are strongly correlated across themetazoan phylogeny, whereas no significant correlation was foundin the control set of proteins. Moreover, we inferred that genomictoolkits required for steroid biosynthesis and action were presentin a basal metazoan, cnidarians. The close similarities betweenvertebrate and sea anemone AR and CYP19 suggest a very ancientorigin of their endocrine functions at the base of metazoanevolution. Finally, we found evidence supporting the hypothesisthat the androgen-to-estrogen ratio determines the gonadal sexin all metazoans.     

雌激素受体Esr1诱导红耳龟早期卵巢分化

为探究3种雌激素受体(estrogen receptor) Esr1、Esr2和Gper1在红耳龟早期胚胎性腺分化中的作用,本研究在分析受体基因表达特征的基础上,通过向性腺分化启动前的产雄温度(male-producing temperature, MPT)龟胚分别注射Esr1、Esr2和Gper1激动剂PPT、WAY 200070和G-1,从性腺形态结构、生殖细胞分布模式、性别分化关键基因和蛋白表达分布方面对处理后的胚胎性腺进行了性逆转分析。表达分析结果显示,esr1在性别分化关键时期性腺中的表达量显著高于esr2和gper1 (表达极低),且呈现产雌温度(female-producing temperature, FPT)性腺高表达。功能验证实验显示,PPT处理后的MPT性腺形态结构明显雌性化,生殖细胞呈现雌性分布模式;雄性分化关键基因dmrt1、amh和sox9 mRNA表达明显下降,雌性分化关键基因foxl2和cyp19a1 mRNA表达则显著上升;Amh和Sox9蛋白表达的荧光信号几乎消失,Foxl2和Arom蛋白被激活出现大量表达,表明性腺由雄性逆转为雌性(性逆转率：70.27%)。而WAY 200070和G-1处理后的MPT性腺仍分化为睾丸,雌雄基因和蛋白的表达及分布与雄性性腺类似。结果表明在红耳龟中,单独激活Esr1能够充分启动早期性腺的雌性分化过程,提示雌激素可能通过其受体1 (Esr1)诱导早期卵巢分化。本研究为进一步解析雌激素在龟性别决定和分化中的调控机制提供了参考。