Cell Polarity and Spindle Position

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DESCRIPTION (provided by applicant): The goal of this project is to comprehensively understand the molecular mechanisms leading to the positioning of the mitotic spindle in the budding yeast Saccaromyces cerevisiae. This process underlies asymmetric cell division and development in many cell types. Spindle positioning involves the interaction of astral microtubules (MTs) with polarized sites on the cell cortex. In many cases, this process also requires the actin cytoskeleton. The capture of MT at the cell cortex shares similarities with the capture of MTs at the kinetochore and some proteins are clearly involved in both processes. Thus, understanding mechanisms for spindle positioning may also impact upon the maintenance of genome stability. Our studies therefore address mechanisms that impact on human health through implications for development and cancer. Our approach utilizes genetic, biochemical, and imaging experiments. It also benefits from our recently solved structure of one component of the system, the Bnil FH2 domain. Building on our previous work to characterize proteins associated with the plus ends of MTs and proteins involved and aspects of actin assembly that are required for spindle orientation we propose experiments with the following aims: Aim1: How is the force generated to orient preanaphase spindles? Aim 2: How is dynein targeted to its site of action and how is dynein activity regulated? Aim 3: How is formin-dependent actin assembly regulated in vivo?