Uterine receptivity to embryo implantation is coordinately regulated by 17β-estradiol (E(2)) and progesterone (P(4)). Although increased E(2) sensitivity causes infertility, the mechanisms underlying the modulation of E(2) sensitivity are unknown. We show that nuclear receptor coactivator-6 (NCOA6), a reported coactivator for estrogen receptor α (ERα), actually attenuates E(2) sensitivity to determine uterine receptivity to embryo implantation under normal physiological conditions. Specifically, conditional knockout of Ncoa6 in uterine epithelial and stromal cells does not decrease, but rather markedly increases E(2) sensitivity, which disrupts embryo implantation and inhibits P(4)-regulated genes and decidual response. NCOA6 enhances ERα ubiquitination and accelerates its degradation, while loss of NCOA6 causes ERα accumulation in stromal cells during the preimplantation period. During the same period, NCOA6 deficiency also caused a failure in downregulation of steroid receptor coactivator-3 (SRC-3), a potent ERα coactivator. Therefore, NCOA6 controls E(2) sensitivity and uterine receptivity by regulating multiple E(2)-signaling components.
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