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INTRACELLULAR ION ENVIRONMENT DURING THE ONTOGENY AS A DETERMINANT OF SEXUAL PHENOTYPE OF RAT BRAIN

个体发育期间细胞内离子环境作为大鼠脑性表型的决定因素

基本信息

批准号：
18390070
负责人：
SAKUMA Yasuo
金额：
$ 11.17万
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：
2006
资助国家：
日本
起止时间：
2006 至 2009
项目状态：
已结题

项目摘要

In the rat, estrogen determines sexual phenotype of the brain, acting at a critical period as neonates. The sexual phenotype thus established persists into adulthood, both in morphology and electrophysiology. In the adults, the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) is larger in males than in females. The anteroventral periventricular nucleus (AVPV) is packed with estrogen receptor (ER) ss-positive neurons in females but these cells scatter in the more lateral areas in males. Estrogen regulates axonal excitability of projection neurons in the ventromedial hypothalamus and those in the preoptic area in diametrically opposite directions in females but not in males. Male phenotype depends on the presence of estrogen as neonates ; the lack leads to the female phenotype. This research project focused intracellular signal cascades, which are kindled by estrogen through estrogen receptor (ER) α and culminate in neurogenesis, migration or cell death. 1) By using 5'-RACE we identified a new leader exon and untranslated internal exons in ERα gene. These exons were used for site-specific transcription of ERα ; 2) In a trait of transgenic rat, which express EGFP under the control of ERα promoter 0/B, ERα-positive neurons in the SDN-POA, but not those in the adjacent areas, were fluorescent. Time lapse movies showed the establishment of the SDN-POA as a result of neuronal migration ; 3) In another trait of transgenic rat, in which gonadotropin-releasing hormone (GnRH) neurons were tagged by EGFP, activation of GABAA_A receptors depolarized adult GnRH neurons due to their high chloride ion content ; 4) DNA microarray, PCR and Western-blot analysis demonstrated site-specific, opposite regulations of apoptosis- and migration-related genes in the SDN-POA and AVPV.

在大鼠中，雌激素决定大脑的性别表型，在新生儿的关键时期起作用。由此建立的性表型在形态学和电生理学上持续到成年期。视前区性二形核（SDN-POA）的体积在成虫中雄性大于雌性。雌激素受体（ER）β-阳性神经元在雌性动物的前腹侧室周核（AVPV）中密集，而在雄性动物中这些细胞分散在更外侧的区域。雌激素调节下丘脑腹内侧投射神经元和视前区投射神经元轴突兴奋性的方向完全相反，在女性，但在男性中没有。雄性表型取决于新生儿雌激素的存在;缺乏导致雌性表型。该研究项目关注细胞内信号级联，其被雌激素通过雌激素受体（ER）α点燃并最终导致神经发生、迁移或细胞死亡。1)利用5 '-RACE技术，我们在ERα基因中发现了一个新的前导外显子和非翻译的内部外显子。2）在ERα启动子0/B调控下表达EGFP的转基因大鼠中，SDN-POA内的ERα阳性神经元呈荧光，而邻近区域的ERα阳性神经元不呈荧光。3）在另一个转基因大鼠的特征中，用EGFP标记促性腺激素释放激素（GnRH）神经元，由于成年GnRH神经元中氯离子含量高，GABAA_A受体的激活使其去极化; 4）DNA微阵列、PCR和Western-blot分析证实SDN-POA和AVPV中凋亡和迁移相关基因的调控具有位点特异性。