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

为了保持基因组信息，染色体必须在细胞分裂时均匀分离。然而，在哺乳动物卵母细胞中，与其他细胞分裂相比，染色体错分离的频率在第一次减数分裂期间非常高。由这些错误产生的非整倍体卵子受精会导致妊娠流产，如果持续到足月，还会导致严重的遗传疾病，如唐氏综合症（21三体）。与有丝分裂一样，卵母细胞减数分裂中染色体分离的保真度至少在一定程度上是由纺锤体组装检查点保证的，纺锤体组装检查点监测着丝点-微管附着。然而，纺锤体检查点可能不是防止卵母细胞中染色体过早分离的唯一机制，因为我们之前基于染色体实时成像的研究清楚地表明，染色体对齐完成后，后期开始有2-3小时的延迟。在此延迟期间，跨越大细胞质的动态肌动蛋白网络将纺锤体从中心移动到卵母细胞的皮质位置，这使得卵母细胞分裂极不对称。因此，在卵母细胞减数分裂中，一个额外的检查点机制可能感知纺锤体的位置并阻止染色体分离，直到纺锤体到达皮质位置，这可能是通过影响纺锤体检查点的活性来实现的。在这个项目中，我们的目标是通过利用我们在SPP第一个资助期建立的实时成像和基因敲低技术，了解哺乳动物卵母细胞第一次减数分裂期间染色体分离时间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.