Conversion of ERalpha cells to ERbeta cells in a cell lineage

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PROJECT SUMMARY / ABSTRACT This study aims to test the hypothesis that an ESR1-expressing cell can be converted to an ESR2-expressing cell and investigate the molecular mechanism that controls the switch. 17β−estradiol (E2) is the key sex hormone regulating development and function of reproductive organs. While two estrogen receptors, ESR1 and ESR2, are well known to be responsible for the classical actions of E2, recent investigations into the functional role of ESR2 show that E2 elicits physiological responses from ESR2-expressing cells that are often completely opposite to those from ESR1-expressing cells. Importantly, while ESR1- and ESR2-expressing cells are co-existent in most of estrogen-responsive organs or tissues, ESR1 and ESR2 are expressed in different cell types. For example, ESR1 is expressed in the surface epithelium and theca cells in the ovary, whereas ESR2 is expressed exclusively in the granulosa cells (GC). No ovarian cell expresses both receptors. We recently made an unexpected observation during a characterization of a transgenic mouse line (Esr1iCreEsr2flox/flox) in which the Esr2 gene was designed to be ablated by a Cre recombinase whose expression was regulated by the endogenous Esr1 gene promoter. In other words, in this transgenic mouse line, the Esr2 gene was deleted in the ESR1 lineage cells. Surprisingly, we found that these transgenic mice were completely deficient of ESR2 expression in the granulosa cells, which otherwise express ESR2 abundantly. This finding indicates that GC lineage cells express ESR1 for some period prior to beginning to express ESR2, evidence of a conversion of ESR1 to ESR2 in the GC lineage. In this study, we will determine exactly when the ESR1 to ESR2 conversion occurs and what underlying mechanism controls the ESR1 and ESR2 expression, using novel transgenic mouse lines that the PI's laboratory generated.