Interacting quantitative trait loci control phenotypic variation in murine estradiol-regulated responses

The steroid hormone estradiol (E2) elicits a spectrum of systemic and uterotropic responses in vivo. For example, E2 treatment of ovariectomized adult and sexually immature rodents leads to uterine leukocytic infiltration, cell proliferation, and organ growth. E2-regulated growth is also associated with a variety of normal and pathological phenotypes. Historically, the uterine growth response has been used as the key model to understand the molecular and biochemical mechanisms underlying E2-dependent growth. In this study, genome exclusion mapping identified two quantitative trait loci (QTL) in the mouse, Est2 and Est3 on chromosomes 5 and 11, respectively, that control the phenotypic variation in uterine wet weight. Both QTL are linked to a variety of E2-regulated genes, suggesting that they may represent loci within conserved gene complexes that play fundamental roles in mediating the effects of E2. Interaction and multiple trait analyses using the uterine leukocyte response and wet weight suggest that Est4, a QTL on chromosome 10, may encode an interacting factor that influences the quantitative variation in both responses. Our results show that E2-dependent responses can be genetically controlled and that a genetic basis may underlie the variation observed in many E2-dependent phenotypes.