Centre de recherché en reproduction et fertilité, Faculté de médicine vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada.
Biol Reprod. 2017 Jul 1;97(1):119-132. doi: 10.1093/biolre/iox060.
Embryonic diapause is a common reproductive strategy amongst mammals, requiring an intimate cross-talk between the endometrium and the blastocyst. To date, the precise molecular signals responsible are unknown in the mouse or any other mammal. Previous studies in the mink implicate polyamines as major regulators of the control of diapause. In the mouse, inhibiting the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC1) during early pregnancy largely prevents implantation, but the fate of the nonimplanted embryos is unknown. To determine whether polyamines control mouse embryonic diapause, we treated pregnant mice with an ODC1 inhibitor from d3.5 to d6.5 postcoitum. At d7.5, 72% of females had no signs of implantation whilst the remaining females exhibited disrupted placental formation and degenerate embryos. In the females with no implantation, we obtained viable blastocysts that had attenuated cell proliferation, indicating a state of diapause. When cultured in vitro, these exhibited trophoblast outgrowth, indicative of reactivation of embryogenesis. In contrast, direct culture of d3.5 blastocysts with an ODC1 inhibitor failed to cause entry into diapause. Examination of the polyamine pathway enzymes and a number of implantation factors indicated inhibition of ODC1 resulted in a uterine phenotype that resembled diapause, with some compensatory increases in crucial genes. Thus, we conclude that an absence or paucity of polyamines induces the uterine quiescence that causes entry of the blastocyst into embryonic diapause.
胚胎休眠是哺乳动物中一种常见的生殖策略，需要子宫内膜和胚泡之间进行密切的交流。迄今为止，在小鼠或任何其他哺乳动物中，负责这种休眠的精确分子信号仍不清楚。先前在水貂中的研究表明，多胺是控制休眠的主要调节剂。在小鼠中，在怀孕早期抑制多胺合成的限速酶——鸟氨酸脱羧酶（ODC1），在很大程度上阻止了着床，但未着床胚胎的命运尚不清楚。为了确定多胺是否控制小鼠胚胎休眠，我们在妊娠第 3.5 天至第 6.5 天用 ODC1 抑制剂处理怀孕的小鼠。在第 7.5 天，72%的雌性动物没有着床的迹象，而其余的雌性动物表现出胎盘形成中断和胚胎退化。在没有着床的雌性动物中，我们获得了具有减弱细胞增殖能力的活胚泡，表明处于休眠状态。当在体外培养时，这些胚泡表现出滋养层的生长，表明胚胎发生的重新激活。相比之下，直接用 ODC1 抑制剂培养第 3.5 天的胚泡未能导致其进入休眠。对多胺途径酶和一些着床因子的检查表明，ODC1 的抑制导致了类似于休眠的子宫表型，一些关键基因的代偿性增加。因此，我们得出结论，多胺的缺乏或不足会导致子宫静止，从而使胚泡进入胚胎休眠。
