Molecular Imaging Provides Novel Insights on Estrogen Receptor Activity in Mouse Brain

Estrogen receptors have long been known to be expressed in several brain areas in addition to those directly involved in the control of reproductive functions. Investigations in humans and in animal models suggest a strong influence of estrogens on limbic and motor functions, yet the complexity and heterogeneity of neural tissue have limited our approaches to the full understanding of estrogen activity in the central nervous system. The aim of this study was to examine the transcriptional activity of estrogen receptors in the brain of male and female mice. Exploiting the ERE-Luc reporter mouse, we set up a novel, bioluminescence-based technique to study brain estrogen receptor transcriptional activity. Here we show, for the first time, that estrogen receptors are similarly active in male and female brains and that the estrous cycle affects estrogen receptor activity in regions of the central nervous system not known to be associated with reproductive functions. Because of its reproducibility and sensitivity, this novel bioluminescence application stands as a candidate as all innovative methodology for the study and development of drugs targeting brain estrogen receptors

Identification of estrogen target genes in human neural cells

In mammals, estrogens have a multiplicity of effects ranging from control of differentiation of selected brain nuclei, reproductive functions, sexual behavior. In addition, these hormones influence the manifestation of disorders like depression and Alzheimer's. Study of the cells target for the hormone has shown that estrogen receptors (ERs) are expressed in all known neural cells, including microglia. In view of the potential interest in the use of estrogens in the therapy of several pathologies of the nervous system, it would be of interest to fully understand the mechanism of estrogen activity in the various neural target cells and get an insight on the molecular means allowing the hormone to display such a variety of effects. We have proposed the use of a reductionist approach for the systematic understanding of the estrogen activities in each specific type of target cell. Thus, we have generated a model system in which to study the activation of one of the known (ERs), estrogen receptor alpha. This system allowed us to identify a number of novel genes which expression may be influenced following the activation of this receptor subtype by estradiol (E-2). We here report on data recently obtained by the study of one of these target genes, nip2, which encodes a proapoptotic protein product. We hypothesize that nip2 might be an important molecular determinant for estrogen anti-apoptotic activity in cells of neural origin and represents a potential target for drugs aimed at mimicking the E-2 beneficial effects in neural cells. (C) 2000 Elsevier Science Ltd. All rights reserved

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

In addition to their well known control of reproductive functions, estrogens modulate important physiological processes. The identification of compounds with tissue-selective activity will lead to new drugs mimicking the beneficial effects of estrogen on the prevention of osteoporosis and cardiovascular or neurodegenerative diseases, while avoiding its detrimental proliferative effects. As an innovative model for the in vivo identification of new selective estrogen receptor modulators (SERMs), we engineered a mouse genome to express a luciferase reporter gene ubiquitously. The constructs for transgenesis consist of the reporter gene driven by a dimerized estrogen-responsive element (ERE) and a minimal promoter. Insulator sequences, either matrix 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 detectable in all 26 tissues examined, but is induced by 17 beta -estradiol (E-2) only in 15 of them, all expressing estrogen receptors (ERs). Immunohistochemical 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 concentration. E-2 activity is blocked by the ER full antagonist ICI 182,780. Tamoxifen shows partial agonist activity in liver and bone when administered to the animals. In the mouse system here illustrated, by biochemical, immunohistochemical, and pharmacological criteria, luciferase content reflects ER transcriptional activity and thus represents a novel system for the study of ER dynamics during physiological fluctuations of estrogen and for the identification of SERMs or endocrine disrupters

Estrogens, apoptosis and cells of neural origin

In mammals, estrogens have a multiplicity of effects in all known neural cells. We review here some of the mechanisms enabling estrogens to differentiate their influence on neural targets. In view of the potential interest in the use of estrogens in the therapy of several pathologies of the nervous system, we have proposed the use of a reductionist approach for the systematic understanding of estrogen activities in each specific type of target cell. We have therefore generated a model system in which to study the activation of one of the known estrogen receptors: estrogen receptor alpha. This system allowed us to identify a number of novel genes, the expression of which may be influenced following the activation of this receptor subtype by estradiol. We here report on preliminary data obtained by the study of one of these target genes, nip2, which encodes a proapoptotic protein product. We hypothesize that Nip2 might be an important molecular determinant for estrogen anti-apoptotic activity in cells of neural origin