Physiological property of estrogen-HEADreceptor positive hypothalamic neurons visualized in transgenic rats

转基因大鼠雌激素-HEAD受体阳性下丘脑神经元的生理特性

基本信息

批准号：
10480227
负责人：
SAKUMA Yasuo
金额：
$ 5.44万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Estrogens are involved in both endocrine and behavioral sex differentiation during brain development and sex-specific regulation of reproductive neuroendocrinology and behavior in adulthood. Cellular estrogen signaling is conveyed by nuclear estrogen receptors (ER) which include the classical ERα as well as the recently cloned ERβ. Both ERs are expressed in the preoptic area (POA), hypothalamus, limbic structures, which have been implicated in the regulation of reproduction. It is controversial, however, whether ERβ is expressed in sex-specific manner like ERα. Co-localization of the two ERs in identical neurons, which would alter the specificity of the transcription by forming heterodimers and produce variable responses to estrogen in different cells depending on the ratios of ERα and ERβ they contain, is also yet to be established.Disruption of either ERα or ERβ by gene targeting affects various aspects of reproduction. Female and male ERα knockout mice are inflertile and ERβ knockou … More t females have a reduced fecundity. Anovulation and hemorrhagic or polycystic ovary are present in either the ERα or ERβ knockout females. The syndrome is due, at least partially, to the central mechanism for the secretion of gonadotropin-releasing hormone (GnRH), because several regimens that decrease gonadotropin secretion ameliorate the defects. Negative feedback action of estrogen on gonadotropin secretion is compromised in ERα-disrupted female and male mice, but progesterone receptor can be induced by estrogen in the POA of male castrates, presumably through ERβ. The major caveat associated with the use of ER knockout mice, however, is that the two ERs may interact to modulate transcriptional activity in certain cells, making separate identification of the action of ERα and ERβ difficult.Estrogen-induced progesterone receptors act as a neuronal transcription factor which triggers GnRH surge in the female rat by altering synthesis or activity of neurotransmitters involved in the regulation of GnRH neurons. Progesterone receptors in the anteroventral periventricular nucleus (AVPV) of the POA may be particularly important. The AVPV is sexually dimorphic with over 3 times as many dopaminergic neurons in the female rat compared with males. The AVPV also contains sexually dimorphic populations of peptidergic neurons or glutamate receptor subunits, and has been implicated in the female-specific ovulatory release of GnRH with its direct projections to GnRH neurons. Indeed, small lesions confined to this region block the cyclic release of gonadotropins in the female rat and culminates in an anovulatory, persistent estrous state. Injections of progesterone receptor antisense oligonucleotides into the third ventricle adjacent to the AVPV blocks the induction of the receptor protein and prevents luteinizing-hormone surge.We found a striking sex difference in the ERβ expression in the AVPV.Neonatal steroid status altered the sexual phenotype. ERβ mRNA co-localized in 84% of estrogen ERα immunoreactive cells, and may be dopaminergic in nature. Infusion of ERβ antisense oligonucleotides into the third ventricle adjacent to the AVPV diminished ERβ protein and produced constant vaginal diestrus. Less

在大脑发育期间，雌激素参与内分泌和行为性别分化，以及对成年后生殖神经内分泌学和行为的性别调节。细胞雌激素信号传导由核雌激素受体（ER）传达，其中包括经典ERα以及最近克隆的ERβ。两种ER都在繁殖调节中实施的po骨前区（POA），下丘脑，边缘结构表达。然而，这是有争议的，是否以ERα等性别特异性表达ERβ。在相同的神经元中，两个ER的共定位将通过形成异二聚体来改变转录的特异性，并根据其所包含的ERα和ERβ的比率产生对不同细胞中雌激素的可变响应，这也尚待确定。基因靶标对ERβ或ERβ的中断影响。基因靶标会影响各个方面的转化方面。雌性和雄性ERα基因敲除小鼠是膨胀的，而ERβ敲除…越来越多的T雌性的繁殖力降低。 ERα或ERβ基因敲除雌性中存在缺乏和出血或多囊卵巢。该综合征至少部分归因于促性腺激素释放马酮（GNRH）的中心机制，因为几种降低促性腺激素分泌的方案可以改善缺陷。雌激素对促性腺激素分泌的负反馈作用在ERα脱离的雌性和雄性小鼠中受到损害，但是孕酮受体可以通过雄性cast骨的POA诱导，大概是通过ERβ诱导的。 The major caveat associated with the use of ER knockout mice, however, is that the two ERs may interact to modulate transcriptional activity in certain cells, making separate identification of the action of ERα and ERβ difficult.Estrogen-induced progesterone receptors act as a neuronal transcription factor which triggers GnRH surge in the female rat by altering synthesis or activity of neurotransmitters involved in the regulation of GnRH neurons. POA前腹膜前核（AVPV）中的孕酮受体可能尤为重要。与雄性相比，AVPV具有性二态性，女性大鼠的多巴胺能神经元的3倍以上。 AVPV还包含肽吉尼神经元或谷氨酸受体亚基的性二态种群，并且在GNRH的女性特异性排卵释放中隐含了其直接对GNRH神经元的项目。实际上，局限于该区域的小病变阻止了雌性大鼠促性腺激素的环状释放，并在发出的持续发情状态下达到顶点。对孕激素受体反义寡核苷酸的注射到与AVPV相邻的第三个心室，阻止了受体蛋白的诱导，并防止了黄体生成激素激增。我们发现AVPV的ERβ表达在AVPV.NEONATAL Stereoid状态中存在惊人的性别差异改变了性现象。 ERβmRNA在84％的雌激素ERα免疫反应性细胞中共定位，并且本质上可能是多巴胺能。将ERβ反义寡核苷酸输注到与AVPV相邻的第三个心室中减少的ERβ蛋白，并产生恒定的阴道外diestrus。较少的