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) α and β. Analysis of knock-out mice devoid of either or both receptor isoforms revealed the essential function of estrogen receptor α in female reproduction, as ERα 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 ERα in specific cell types of the body. Using cell-type-specific ERα mutants, it could be shown that ERα in neurons is essential for the luteinizing hormone (LH) surge that triggers ovulation. Studies using ERα and ERβ-selective agonists reveal that ERα 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.