Kawata Yui, Terakawa Jumpei, Takeshita Ayuu, Namiki Takafumi, Kageyama Atsuko, Noguchi Michiko, Murakami Hironobu, Fukada Toshiyuki, Ito Junya, Kashiwazaki Naomi
Laboratory of Animal Reproduction, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara 252-5201, Japan.
Graduate School of Veterinary Science, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara 252-5201, Japan.
PNAS Nexus. 2025 Feb 10;4(2):pgaf047. doi: 10.1093/pnasnexus/pgaf047. eCollection 2025 Feb.
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 , 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. 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.
锌是一种关键的微量元素，对包括男性和女性生殖系统在内的各种生物学功能都很重要，但生育能力背后的分子机制尚不清楚。我们在此表明，子宫内膜组织中的锌信号对于小鼠成功怀孕是不可或缺的。我们观察到，子宫特异性基因缺失（该基因编码一种锌转运蛋白以提高细胞质锌水平）会导致雌性不育，原因是胚胎无法侵入子宫内膜并随后发生胚胎丢失。ZIP10 mRNA在子宫组织中表达，尤其是在胚胎植入期间的蜕膜化基质细胞中。ZIP10的缺失会导致上皮和基质之间孕酮-孕酮受体（PGR）信号减弱，包括体内上皮和基质中PGR及其靶分子的异常表达。我们发现，由于ZIP10缺失导致的细胞质锌离子耗竭会破坏GLI1核-质定位的变化，这不仅在小鼠而且在人类中对于体外蜕膜化基质细胞中的PGR信号传导至关重要。我们的研究结果（i）突出了ZIP10介导的锌稳态调节在成功怀孕建立中的生物学相关性，（ii）将有助于预防人类不育。
