Université de Montpellier, Centre de Recherche de Biologie Cellulaire de Montpellier, CNRS UMR 5237, 1919 Route de Mende, 34293 Montpellier Cedex 5, France.
Unité de Cytogénétique DPI, CHU Arnaud de Villeneuve, 34295 Montpellier Cedex 5, France.
Sci Rep. 2017 Mar 13;7:44001. doi: 10.1038/srep44001.
In human eggs, aneuploidy increases with age and can result in infertility and genetic diseases. Studies in mouse oocytes suggest that reduced centromere cohesion and spindle assembly checkpoint (SAC) activity could be at the origin of chromosome missegregation. Little is known about these two features in humans. Here, we show that in human eggs, inter-kinetochore distances of bivalent chromosomes strongly increase with age. This results in the formation of univalent chromosomes during metaphase I (MI) and of single chromatids in metaphase II (MII). We also investigated SAC activity by checking the localization of BUB1 and BUBR1. We found that they localize at the kinetochore with a similar temporal timing than in mitotic cells and in a MPS1-dependent manner, suggesting that the SAC signalling pathway is active in human oocytes. Moreover, our data also suggest that this checkpoint is inactivated when centromere cohesion is lost in MI and consequently cannot inhibit premature sister chromatid separation. Finally, we show that the kinetochore localization of BUB1 and BUBR1 decreases with the age of the oocyte donors. This could contribute to oocyte aneuploidy.
在人类卵子中，非整倍体随着年龄的增长而增加，可能导致不孕和遗传疾病。对小鼠卵母细胞的研究表明，着丝粒凝聚力和纺锤体检查点（SAC）活性的降低可能是染色体错误分离的根源。关于这两个特征在人类中的情况知之甚少。在这里，我们表明，在人类卵子中，二价染色体的动粒间距离随着年龄的增长而强烈增加。这导致在减数分裂 I（MI）中形成单价染色体，在减数分裂 II（MII）中形成单个染色单体。我们还通过检查 BUB1 和 BUBR1 的定位来研究 SAC 活性。我们发现它们与有丝分裂细胞相似的时间在动粒上定位，并且以 MPS1 依赖性的方式定位，这表明 SAC 信号通路在人类卵母细胞中是活跃的。此外，我们的数据还表明，当 MI 中着丝粒凝聚力丧失时，该检查点失活，因此不能抑制姐妹染色单体过早分离。最后，我们表明 BUB1 和 BUBR1 的动粒定位随着卵母细胞供体年龄的增长而降低。这可能导致卵母细胞非整倍体。
