Nuclear Receptor Coactivator-6 Attenuates Uterine Estrogen Sensitivity to Permit Embryo Implantation

SummaryUterine receptivity to embryo implantation is coordinately regulated by 17β-estradiol (E2) and progesterone (P4). Although increased E2 sensitivity causes infertility, the mechanisms underlying the modulation of E2 sensitivity are unknown. We show that nuclear receptor coactivator-6 (NCOA6), a reported coactivator for estrogen receptor α (ERα), actually attenuates E2 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 E2 sensitivity, which disrupts embryo implantation and inhibits P4-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 E2 sensitivity and uterine receptivity by regulating multiple E2-signaling components.

► Ncoa6 loss in the uterus disrupts embryo implantation by increasing E2 sensitivity
► Ncoa6 loss upregulates stromal ERα and epithelial SRC-3 in early pregnant uteri
► Ncoa6 promotes ERα ubiquitination and degradation
► The “coactivator” Ncoa6 actually attenuates ERα function in the uterus