We have cloned a novel member of the nuclear receptor superfamily.

During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ERα and ERβ) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.

Estrogens inf luence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ER␣ and ER␤. We previously generated and studied knockout mice lacking estrogen receptor ␣ and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor ␤ Estrogens are critical to the functioning and maintenance of a diverse array of tissues and physiological systems in mammals. The actions of estrogen on such classical targets as the reproductive tract, gonads, mammary tissue, and hypothalamic͞pituitary axis have been well characterized. A role in nonreproductive tissues, such as maintenance of bone mineral density and cardiovascular health in women, also has been described (1, 2). The physiological responses to estrogen are known to be mediated within specific tissues by at least two estrogen receptors (ERs), ER␣ and ER␤ (3-5). The ERs are a class I member of the nuclear hormone receptor family and act as ligand-activated nuclear transcription factors (6). Studies of the receptors' tissue distribution and expression pattern indicate that ER␣ has a broad expression pattern, whereas ER␤ has a more focused pattern with high levels in the ovary, prostate, epididymis, lung, and hypothalamus (7,8). However, the exact physiological responses attributable to each receptor are unknown. We previously described the pleiotropic effects of disruption of the ER␣ gene in ER␣ knockout mice (␣ERKO), including absence of breast development in females and infertility caused by reproductive tract and gonadal and behavioral abnormalities in both sexes (9-13). Here, we describe the generation of mice homozygous for a disruption of the ER␤ gene; initial characterizations indicate that the ER␤ Ϫ͞Ϫ mice exhibit phenotypes that are distinct from those of the ␣ERKO mice.