Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
J Clin Invest. 2011 Jan;121(1):318-27. doi: 10.1172/JCI44723. Epub 2010 Dec 6.
During intrauterine life, the mammalian embryo survives via its physical connection to the mother. The uterine decidua, which differentiates from stromal cells after implantation in a process known as decidualization, plays essential roles in supporting embryonic growth before establishment of the placenta. Here we show that female mice lacking death effector domain-containing protein (DEDD) are infertile owing to unsuccessful decidualization. In uteri of Dedd-/- mice, development of the decidual zone and the surrounding edema after embryonic implantation was defective. This was subsequently accompanied by disintegration of implantation site structure, leading to embryonic death before placentation. Polyploidization, a hallmark of mature decidual cells, was attenuated in DEDD-deficient cells during decidualization. Such inefficient decidualization appeared to be caused by decreased Akt levels, since polyploidization was restored in DEDD-deficient decidual cells by overexpression of Akt. In addition, we showed that DEDD associates with and stabilizes cyclin D3, an important element in polyploidization, and that overexpression of cyclin D3 in DEDD-deficient cells improved polyploidization. These results indicate that DEDD is indispensable for the establishment of an adequate uterine environment to support early pregnancy in mice.
在子宫内，哺乳动物胚胎通过与母体的物理连接而存活。蜕膜在着床后从基质细胞分化而来，在胎盘建立之前对支持胚胎生长起着至关重要的作用。在这里，我们发现缺乏死亡效应结构域蛋白（DEDD）的雌性小鼠由于蜕膜化不成功而不育。在 Dedd-/- 小鼠的子宫中，胚胎植入后的蜕膜区和周围水肿的发育存在缺陷。随后，着床部位结构解体，导致胎盘形成前胚胎死亡。多倍体化是成熟蜕膜细胞的标志，在蜕膜化过程中 DEDD 缺失细胞中的多倍体化减弱。这种低效的蜕膜化似乎是由于 Akt 水平降低引起的，因为在 DEDD 缺失的蜕膜细胞中过表达 Akt 可以恢复多倍体化。此外，我们还表明 DEDD 与细胞周期蛋白 D3 （多倍体化的重要因素）结合并稳定其表达，并且在 DEDD 缺失细胞中过表达细胞周期蛋白 D3 可改善多倍体化。这些结果表明，DEDD 对于建立足够的子宫环境以支持小鼠早期妊娠是必不可少的。
