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

减数分裂中同源染色体分离与不对称分裂的协调机制

• 批准号: 118988675
• 负责人: Dr. Jan Ellenberg
• 金额: --
• 依托单位: Europäisches Laboratorium für Molekularbiologie (EMBL)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/118988675?language=en
• 关键词: Mechanism; coordination; homologous; chromosome; segregation

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.

为了保持基因组信息，染色体必须在细胞分裂过程中均匀分离。然而，在哺乳动物卵母细胞中，已知与其他细胞分裂相比，在第一次减数分裂期间染色体错误分离的频率极高。由这种错误产生的非整倍体卵子受精会导致妊娠失败，如果服务到足月，会导致严重的遗传疾病，如唐氏综合征（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部分地由监测动粒-微管附着的纺锤体组装检查点来确保。然而，纺锤体检查点可能不是防止卵母细胞中早熟染色体分离的唯一机制，因为我们先前基于染色体实时成像的研究清楚地表明，在染色体比对完成后，后期开始延迟2-3小时。在此延迟期间，一个动态的肌动蛋白网络跨越整个大的细胞质移动纺锤体从中心到卵母细胞的皮质位置，这使得卵母细胞分裂非常不对称。因此，在卵母细胞减数分裂中，额外的检查点机制可能感测纺锤体的位置，并防止染色体分离，直到纺锤体到达皮质位置，可能通过影响纺锤体检查点活性。本项目利用SPP第一个资助期建立的活体成像技术和基因敲除技术，研究哺乳动物卵母细胞第一次减数分裂中纺锤体位置控制染色体分离的分子机制。