Mechanism of the coordination of homologous chromosome segregation with asymmetric division in meiosis I

为了保持基因组信息，在细胞分裂过程中，染色体必须均匀分离。然而，在哺乳动物卵母细胞中，与其他细胞分裂相比，在第一次减数分裂中染色体错误分离的频率非常高。由这些错误产生的非整倍体卵子受精会导致妊娠损失，如果提供给足月，还会导致严重的遗传疾病，如唐氏综合症(21三体)。正如在有丝分裂中一样，卵母细胞减数分裂中染色体分离的保真度至少部分是通过监测着丝粒-微管附着的纺锤体组装检查点来确保的。然而，纺锤体检查点可能不是防止卵母细胞染色体早熟分离的唯一机制，因为我们之前基于染色体活体成像的研究清楚地表明，在完成染色体比对后，后期开始有2-3小时的延迟。在这一延迟期间，一个动态的肌动蛋白网络横跨整个大细胞质，将纺锤体从中心移动到卵母细胞的皮质位置，这使得卵母细胞能够极不对称地分裂。因此，在卵母细胞减数分裂中，一个额外的检查点机制可能会感知纺锤体的位置，防止染色体分离，直到纺锤体达到皮质位置，这可能是通过影响纺锤体检查点的活动。在这个项目中，我们利用我们在SPP的第一个资助期建立的实时成像和基因敲除技术，旨在了解哺乳动物卵母细胞第一次减数分裂过程中，染色体分离的时机是如何由纺锤体位置控制的分子机制。

To maintain genomic information, chromosomes must be segregated equally during cell division. However in mammalian oocytes, it is known that the frequency of chromosome missegregation is extremely high during the first meiotic division compared to other cell divisions. Fertilization of aneuploid eggs generated by such errors results in pregnancy loss and, if servived to term, severe genetic disorders such as Down's syndrome (trisomy 21). As in mitosis, the fidelity of chromosome segregation in oocyte meiosis is ensured, at least in part, by the spindle assembly checkpoint which monitors kinetochore--‐microtubule attachment. However, the spindle checkpoint may not be the sole mechanism to prevent precocious chromosome segregation in oocytes, because our previous studies based on live imaging of chromosomes clearly showed that there is a 2-3 hour delay in anaphase onset after completion of chromosome alignment. During this delay, a dynamic actin network spanning throughout the large cytoplasm moves the spindle from the center into the cortical position of the oocyte, which allows the oocyte to divide extremely asymmetrically. Thus, in oocyte meiosis, an additional checkpoint mechanism may sense the position of the spindle and prevent chromosome segregation until the spindle reaches the cortical position, potentially by affecting spindle checkpoint activity. In this project, we aim to understand the molecular mechanism how the timing of chromosome segregation is controlled by the spindle position during the first meiotic division of mammalian oocytes, by taking advantage of the live imaging and gene knock down tech-niques we established during the first funding period of the SPP.