Interacting quantitative trait loci control phenotypic variation in murineestradiol-regulated responses

The steroid hormone estradiol (E-2) elicits a spectrum of systemic and uter otropic responses in vivo. For example, E-2 treatment of ovariectomized adu lt and sexually immature rodents leads to uterine leukocytic infiltration, cell proliferation, and organ growth. E-2-regulated growth is also associat ed with a variety of normal and pathological phenotypes. Historically, the uterine growth response has been used as the key model to understand the mo lecular and biochemical mechanisms underlying E-2-dependent growth. In this study, genome exclusion mapping identified two quantitative trait loci (QT L) 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 E-2-regulated genes, suggesting that they may represent lo ci within conserved gene complexes that play fundamental roles in mediating the effects off,. Interaction and multiple trait analyses using the uterin e leukocyte response and wet weight suggest that Est4, a QTL on chromosome 10, may encode an interacting factor that influences the quantitative varia tion in both responses. Our results show that E-2-dependent responses can b e genetically controlled and that a genetic basis may underlie the variatio n observed in many E-2-dependent phenotypes.