Lightfoot Daniel A, Kouznetsova Anna, Mahdy Ensaf, Wilbertz Johannes, Höög Christer
Department of Cell and Molecular Biology and Center for Genomics and Bioinformatics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Dev Biol. 2006 Jan 15;289(2):384-94. doi: 10.1016/j.ydbio.2005.11.001. Epub 2005 Dec 9.
More than any other species, humans have difficulty reproducing. As recent studies show that human infertility is ever increasing, much efforts are needed towards the understanding of our low fecundity. While aneuploidy is the leading cause of spontaneous pregnancy loss in humans, we still know surprisingly little about the developmental consequences of chromosomal abnormalities. We have here used a mouse model that spontaneously incites chromosomal primary aneuploidy in female haploid oocytes and find that after fertilization, these primary aneuploid cells become cytological unstable, generating diverse karyotypic mosaic embryos. The mosaic aneuploid embryos can develop and implant into the female uterine tissue and initiate the gastrulation process (E6.5) but quickly degrade and succumb by E8.0. We find that loss of embryo viability due to chromosomal mosaicism is caused by the activation of a spatially and temporally controlled p53-independent apoptotic mechanism and does not result from a failure to progress through mitosis. We conclude that an initial state of primary aneuploidy within an embryo results in a rapid evolution of mosaicism and early embryonic death. This gestational loss due to aneuploid mosaicism could account for the large proportion of human pregnancy loss prior to clinical recognition.
与其他任何物种相比，人类在繁殖方面存在困难。近期研究表明，人类不孕问题日益严重，因此需要付出更多努力来了解我们低生育力的原因。虽然非整倍体是人类自然流产的主要原因，但令人惊讶的是，我们对染色体异常的发育后果仍然知之甚少。我们在此使用了一种小鼠模型，该模型能在雌性单倍体卵母细胞中自发引发染色体原发性非整倍体，结果发现受精后，这些原发性非整倍体细胞变得细胞学不稳定，产生了各种核型的嵌合胚胎。嵌合非整倍体胚胎能够发育并植入雌性子宫组织，启动原肠胚形成过程（E6.5），但在E8.0时会迅速退化并死亡。我们发现，由于染色体嵌合导致的胚胎活力丧失是由一种在空间和时间上受到控制的、不依赖p53的凋亡机制激活引起的，而不是由于有丝分裂进程失败导致的。我们得出结论，胚胎内原发性非整倍体的初始状态会导致嵌合现象迅速演变和早期胚胎死亡。这种由非整倍体嵌合引起的妊娠丢失可能占临床确诊前人类妊娠丢失的很大比例。
