Estrogen Receptor Beta Splice Variants and Brain Development

海马体是哺乳动物大脑中参与认知功能的一部分，对类固醇激素雌激素也很敏感。已知雌激素影响海马体的性别分化，但这种发育的分子机制尚不清楚。在发育过程中，海马区雌激素受体(ER)分子的数量增加，这是由ER的α和β两种形式的瞬时表达触发的，这表明可能是雌激素作用的一个新的关键期。ER-β的瞬时表达主要是一种称为-delta3(-d3)的异构体剪接变异体，它通过一种独特的分子机制来调节靶基因，不同于经典描述的雌激素反应元件(ERE)。该项目使用分子生物学来检测这些ER-β-d3剪接变异体的体外功能。瞬时转染、报告基因分析和其他转录和运输分析将确定-d3变体如何驱动转录并与其他调节蛋白和其他ER受体类型相互作用。该项目还将在体外看到的影响与在活体动物中看到的正常生理事件联系起来。这些结果将阐明雌激素如何影响海马体发育的新机制，并将超越神经内分泌学、发育生物学和潜在的认知神经科学而具有重要意义。该项目还包括在良好的实验室研究环境中培训本科生和研究生。

The hippocampus, a part of the mammalian brain involved in cognitive functions, is also sensitive to the steroid hormone estrogen. Estrogen is known to influence the sexual differentiation of the hippocampus, but the molecular mechanisms for this development are not clear. Numbers of estrogen receptor (ER) molecules in the hippocampus increase during development, triggered by transient expression of both the alpha and beta forms of ER, which suggests a possible novel critical period for estrogen action. The transient expression of ER-beta is predominantly of an isoform splice variant termed -delta 3 (-d3), which acts through a unique molecular mechanism to regulate target genes, unlike the classically described estrogen-response element (ERE). This project uses molecular biology to examine the function in vitro of these -d3 splice variants of ER-beta. Transient transfection, reporter gene analysis, and other transcription and trafficking assays will determine how -d3 variants drive transcription and interact with other regulatory proteins and other ER receptor types. The project also bridges the effects seen in vitro with those normal physiological events seen in the living animal. Results will clarify a novel mechanism of how estrogens affect hippocampal development, and will be important beyond neuroendocrinology, on developmental biology and potentially on cognitive neuroscience. The project also involves training undergraduates and graduate students in an excellent laboratory research environment.