Endometrial zinc transporter Slc39a10/Zip10 is indispensable for progesterone responsiveness and successful pregnancy in mice.

Zinc is a critical trace element that is important for various biological functions including male and female reproductive systems, but the molecular mechanisms that underlie fertility have been unclear. We show here that zinc signaling in the endometrial tissue is indispensable for successful pregnancy in mice. We observed that a uterine-specific genetic deletion of Slc39a10/Zip10, which encodes one of the zinc transporters to elevate the cytoplasmic level of zinc, results in female infertility due to failure of embryo invasion into the endometrium and subsequent embryonic loss. Zip10 mRNA is expressed in uterine tissues, especially in the decidualizing stromal cells during embryo implantation. The absence of ZIP10 leads to attenuation of progesterone-progesterone receptor (PGR) signals between the epithelium and the stroma, including abnormal expression of the PGR and its target molecules in both the epithelium and stroma in vivo. We found that depletion of intracytoplasmic zinc ions due to loss of ZIP10 disrupts the change in nuclear-to-cytoplasmic localization of GLI1, which is critical for PGR signaling in the decidualizing stromal cells in vitro not only in mice but also in humans. Our findings (i) highlight a biological relevance of ZIP10-mediated zinc homeostatic regulation in the establishment of a successful pregnancy and (ii) will help to prevent infertility in humans.