The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Nature. 2018 Mar 22;555(7697):463-468. doi: 10.1038/nature26002. Epub 2018 Mar 14.
Large-scale phenotyping efforts have demonstrated that approximately 25-30% of mouse gene knockouts cause intrauterine lethality. Analysis of these mutants has largely focused on the embryo and not the placenta, despite the crucial role of this extraembryonic organ for developmental progression. Here we screened 103 embryonic lethal and sub-viable mouse knockout lines from the Deciphering the Mechanisms of Developmental Disorders program for placental phenotypes. We found that 68% of knockout lines that are lethal at or after mid-gestation exhibited placental dysmorphologies. Early lethality (embryonic days 9.5-14.5) is almost always associated with severe placental malformations. Placental defects correlate strongly with abnormal brain, heart and vascular development. Analysis of mutant trophoblast stem cells and conditional knockouts suggests that a considerable number of factors that cause embryonic lethality when ablated have primary gene function in trophoblast cells. Our data highlight the hugely under-appreciated importance of placental defects in contributing to abnormal embryo development and suggest key molecular nodes that govern placenta formation.
大规模表型分析研究表明，大约 25%-30%的小鼠基因敲除会导致宫内致死。尽管胎盘对于胚胎发育至关重要，但这些突变体的分析主要集中在胚胎上，而不是胎盘上。在这里，我们对发育障碍解析计划中的 103 条胚胎致死和亚致死的小鼠基因敲除系进行了胎盘表型筛选。我们发现，在妊娠中期或之后致死的敲除系中，有 68%表现出胎盘畸形。早期致死（胚胎第 9.5-14.5 天）几乎总是与严重的胎盘畸形有关。胎盘缺陷与脑、心脏和血管发育异常密切相关。对突变滋养层干细胞和条件性敲除的分析表明，当大量导致胚胎致死的因子被剔除时，它们在滋养层细胞中有主要的基因功能。我们的数据突出了胎盘缺陷在导致胚胎发育异常方面的重要性，这表明了控制胎盘形成的关键分子节点。
