Homolog bi-orientation and segregation in oocyte acentrosomal meiosis

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In the first meiotic division, homologous chromosomes linked by chiasmata attach to microtubules from opposite poles of the spindle (bi-orientation) and then segregate. Errors in chromosome segregation in the oocyte lead to aneuploidy and are the leading cause of miscarriage, infertility and birth defects. In the oocytes of many organisms, including mammals and insects, meiotic spindle assembly occurs in the absence of centrosomes. We use Drosophila melanogaster females as a model to understand the mechanisms that promote accurate chromosome segregation on the acentrosomal spindle of oocytes. We are interested in understanding the mechanisms of bi-orientation and the features of the oocyte spindle that make it susceptible to chromosome segregation errors. From our previous research we have shown that the kinetochore interacts with the microtubules in two ways. First, lateral attachments, where the kinetochores move along the sides of microtubules, establish bi-orientation. Second, end-on attachments, where the kinetochores make a stable attachment to the ends of microtubules, maintain connections to a pole and segregate the homologs. Stabilizing end-on attachments too rapidly leads to errors in chromosome segregation. The lateral interactions important for bi-orientation occur between the kinetochores and central spindle, which are composed of overlapping antiparallel microtubules and may be particularly important for acentrosomal oocytes. Our proposed studies are focused on understanding how the kinetochores and central spindle interact to regulate the transition from lateral to end-on attachments and accurately segregate chromosomes. 1) Investigate the mechanisms of meiotic kinetochore assembly 2) Investigate how the meiotic kinetochore ensures accurate bi-orientation 3) Investigate how the central spindle interacts with kinetochores and promotes bi-orientation These three Aims are linked by a goal to understand the mechanisms of chromosome segregation important to oocytes. In completing this work, we will have identified mechanisms required for kinetochore assembly and for regulating the transition from lateral and end-on kinetochore-microtubule attachments. We will also determine the role of the central spindle in this process, which we believe is a mechanism of bi-orientation that is particularly important in acentrosomal oocytes.