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

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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.