The role of microtubule dynamics in midzone driven chromosome segregation in anaphase

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Summary The faithful segregation of chromosomes during mitosis is a fundamental and important process, happening approximately a quadrillion time throughout a human life span. Errors in mitosis have severe implications and are often detrimental to development, health and survival of the organism. Microtubules are the main building blocks of mitotic spindles and are a very important target for cancer therapy. We know that microtubules, in particular kinetochore microtubules, exert forces on chromosomes to initially position them on the metaphase plate and consequently divide them to the two daughter cells. However, recent research has shown that the central spindle also plays an important role in chromosome segregation. The precise mechanisms of how the central spindle regulates chromosome segregation are not fully understood today. A line of evidence has suggested that the central spindle can generate outward pushing forces to move chromosomes, but it has also been convincingly shown to slow chromosome segregation down by acting like a break. The goal of this proposal is to dissect the function of the central spindle during anaphase and to identify how the central spindle generates forces contributing to the segregation of chromosomes. We further aim to establish the contribution of microtubule dynamics for central spindle function. To achieve this goal, we use the microstructural data from tomography in wild type and mutant conditions to monitor the microtubule arrangement and properties in the central spindle during anaphase and to identify potential interactions and force generating mechanisms. We will complement the precise structural data with dynamic data on microtubules in the midzone obtained by cutting edge light-microscopic analysis. We will use mathematical modeling to develop and test hypothesis of how the spindle midzone contributes to chromosome segregation in anaphase. The ultimate goal of our study is to understand how the central spindle generates forces that regulate the segregation of chromosomes and to identify the molecular key players of this process