Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene
Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene
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DOI：
10.1073/pnas.0902925106
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发表时间：
2009-07-21
影响因子：
11.1
通讯作者：
Heidmann, Thierry
中科院分区：
文献类型：
--
作者：
Dupressoir, Anne;Vernochet, Cecile;Heidmann, Thierry
在大多数哺乳动物物种中，胎盘发育的关键过程是滋养层细胞融合成高度特化的多核合胞体滋养层，大多数母胎交换通过该层进行。尽管最近鉴定了2对逆转录病毒来源的包膜基因，但对该过程知之甚少，所述包膜基因独立地由人（合胞素-1和合胞素-2）和小鼠（合胞素-A和合胞素-B）基因组获得，特异性地在胎盘中表达，并且具有体外细胞-细胞融合活性。通过产生基因敲除小鼠，我们在这里显示，纯合合胞素-A无效小鼠胚胎在妊娠11.5和13.5天之间在子宫内死亡。精细的细胞和亚细胞分析的合胞素-A缺陷胎盘披露特定的破坏结构的合胞滋养层包含迷宫，与滋养层细胞未能融合成interhemal合胞体层。缺乏合胞素-A介导的滋养层细胞融合与细胞过度扩张有关，其代价是胎儿血管空间和细胞凋亡，增加了观察到的母胎界面结构缺陷，引起血管形成减少，胎盘运输抑制和胎儿生长迟缓，最终导致胚胎死亡。这些结果表明，合胞素-A是必不可少的滋养层细胞分化和合胞滋养层形态发生在胎盘发育过程中，他们提供的证据表明，从祖先逆转录病毒捕获的基因已在收购新的，重要的功能在哺乳动物进化的关键。
In most mammalian species, a key process of placenta development is the fusion of trophoblast cells into a highly specialized, multinucleated syncytiotrophoblast layer, through which most of the maternofetal exchanges take place. Little is known about this process, despite the recent identification of 2 pairs of envelope genes of retroviral origin, independently acquired by the human (syncytin-1 and syncytin-2) and mouse (syncytin-A and syncytin-B) genomes, specifically expressed in the placenta, and with in vitro cell-cell fusion activity. By generating knockout mice, we show here that homozygous syncytin-A null mouse embryos die in utero between 11.5 and 13.5 days of gestation. Refined cellular and subcellular analyses of the syncytin-A-deficient placentae disclose specific disruption of the architecture of the syncytiotrophoblast-containing labyrinth, with the trophoblast cells failing to fuse into an interhemal syncytial layer. Lack of syncytin-A-mediated trophoblast cell fusion is associated with cell overexpansion at the expense of fetal blood vessel spaces and with apoptosis, adding to the observed maternofetal interface structural defects to provoke decreased vascularization, inhibition of placental transport, and fetal growth retardation, ultimately resulting in death of the embryo. These results demonstrate that syncytin-A is essential for trophoblast cell differentiation and syncytiotrophoblast morphogenesis during placenta development, and they provide evidence that genes captured from ancestral retroviruses have been pivotal in the acquisition of new, important functions in mammalian evolution.