Engineering of a mouse for the in vivo profiling of estrogen receptor activity

In addition to their well known control of reproductive functions, estrogen s modulate important physiological processes. The identification of compoun ds with tissue-selective activity will lead to new drugs mimicking the bene ficial effects of estrogen on the prevention of osteoporosis and cardiovasc ular or neurodegenerative diseases, while avoiding its detrimental prolifer ative effects. As an innovative model for the in vivo identification of new selective estrogen receptor modulators (SERMs), we engineered a mouse geno me to express a luciferase reporter gene ubiquitously. The constructs for t ransgenesis consist of the reporter gene driven by a dimerized estrogen-res ponsive element (ERE) and a minimal promoter. Insulator sequences, either m atrix attachment region (MAR) or beta -globin hypersensitive site 4 (HS4), flank the construct to achieve a generalized, hormone-responsive luciferase expression. In the mouse we generated, the reporter expression is detectab le in all 26 tissues examined, but is induced by 17 beta -estradiol (E-2) o nly in 15 of them, all expressing estrogen receptors (ERs). Immunohistochem ical studies show that in the mouse uterus, luciferase and ERs colocalize. In primary cultures of bone marrow cells explanted from the transgenic mice and in vivo, luciferase activity accumulates with increasing E-2 concentra tion. E-2 activity is blocked by the ER full antagonist ICI 182,780. Tamoxi fen shows partial agonist activity in liver and bone when administered to t he animals. In the mouse system here illustrated, by biochemical, immunohis tochemical, and pharmacological criteria, luciferase content reflects ER tr anscriptional activity and thus represents a novel system for the study of ER dynamics during physiological fluctuations of estrogen and for the ident ification of SERMs or endocrine disrupters.