Genetic dissection of estrogen receptor signaling in vivo.

The multiple actions of estrogen in mammalian physiology are brought about, on a molecular level, by several signaling pathways, and mediated by at least two receptors-estrogen receptor (ER) alpha and beta. Analysis of knock-out mice devoid of either or both receptor isoforms revealed the essential function of estrogen receptor alpha in female reproduction, as ERalpha deficiency leads to a complex endocrine phenotype, severe disturbances in several reproductive organs, and infertility. This reflects the many actions of estrogen in female reproductive endocrinology. To carry the understanding of estrogen action to a cellular resolution, modern genetic technologies can be employed, including artificial chromosome-based transgenesis and conditional gene targeting. The combination of these techniques yields mouse models that lack ERalpha in specific cell types of the body. Using cell-type-specific ERalpha mutants, it could be shown that ERa in neurons is essential for the luteinizing hormone (LH) surge that triggers ovulation. Studies using ERalpha and ERbeta-selective agonists reveal that ERalpha activation is sufficient to induce an ovulatory hormonal stimulus. Thus, genetic analysis and selective pharmacological tools can complement each other in the molecular and cellular dissection of hormone receptor function in vivo.