Estrogen Receptor Beta Splice Variants and Brain Development

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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.