A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast
A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast
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DOI：
10.1073/pnas.1112304108
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发表时间：
2011-11-15
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，胎盘发育的关键步骤是滋养层细胞融合成多核合体滋养层，实现基本的母胎交换功能。对这一过程的关键见解来自于逆转录病毒起源的包膜基因的发现，即由人类（合胞素-1和-2）、小鼠（合胞素-A和-B）和兔（合胞素-Ory 1）基因组独立获得的具有融合特性和胎盘特异性表达的合胞素。我们以前表明，小鼠合胞素-A是必不可少的两个合胞滋养层之一的形成和胚胎存活。在这里，我们已经产生了合胞素-B基因敲除小鼠，并证明合胞素-B无效胎盘显示受损的形成合胞体滋养层II（ST-II），与未融合的贴壁细胞的证据，并扩大母体腔隙破坏胎盘结构。出乎意料的是，合胞素B无效胚胎是可行的，只有有限的迟发性生长迟缓和减少新生儿数量。微阵列分析确定了突变胎盘中连接蛋白30基因的上调，该蛋白定位于母胎界面，表明间隙连接介导的代偿机制。最后，如果合胞素B缺失，双KO小鼠显示合胞素A缺失胚胎的过早死亡，表明ST-I和ST-II之间的合作。这些研究结果表明，这两个内源性逆转录病毒衍生的合胞素基因有助于独立的胎盘形成过程中的两个合胞滋养层的形成，证明了逆转录病毒基因捕获的主要作用，通过趋同进化，产生多个胎盘结构。虽然有些是完成妊娠所绝对需要的，但其他一些仍然可以进行“表观遗传”补偿，从而说明了胎盘进化过程中分子机制的复杂性。
In most mammalian species, a critical step of placenta development is the fusion of trophoblast cells into a multinucleated syncytiotrophoblast layer fulfilling essential fetomaternal exchange functions. Key insights into this process came from the discovery of envelope genes of retroviral origin, the syncytins, independently acquired by the human (syncytin-1 and -2), mouse (syncytin-A and -B), and rabbit (syncytin-Ory1) genomes, with fusogenic properties and placenta-specific expression. We previously showed that mouse syncytin-A is essential for the formation of one of the two syncytiotrophoblast layers and for embryo survival. Here, we have generated syncytin-B KO mice and demonstrate that syncytin-B null placenta displays impaired formation of syncytiotrophoblast layer II (ST-II), with evidence of unfused apposed cells, and enlargement of maternal lacunae disrupting the placenta architecture. Unexpectedly, syncytin-B null embryos are viable, with only limited late-onset growth retardation and reduced neonate number. Microarray analyses identified up-regulation of the connexin 30 gene in mutant placentae, with the protein localized at the fetomaternal interface, suggesting gap junction-mediated compensatory mechanisms. Finally, double-KO mice demonstrate premature death of syncytin-A null embryos if syncytin-B is deleted, indicating cooperation between ST-I and ST-II. These findings establish that both endogenous retrovirus-derived syncytin genes contribute independently to the formation of the two syncytiotrophoblast layers during placenta formation, demonstrating a major role of retroviral gene capture, through convergent evolution, to generate multiple placental structures. Although some are absolutely required for completion of pregnancy, others are still amenable to "epigenetic" compensations, thus illustrating the complexity of the molecular machinery that developed during placental evolution.