Patterning acentrosomal microtubule arrays

Yale University, New Haven CT

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Abstract

Abstract The microtubule cytoskeleton supports cell-division, cellular morphology and intracellular cargo transport. While the centrosome is a major site of microtubule nucleation in dividing cells, many differentiated cells harbor acentrosomal microtubule arrays. Prominent examples include germline cells, plant epidermis, epithelia and neurons. To understand cellular differentiation, it is crucial to learn how acentrosomal array architecture is set up to achieve a specific pattern of polymer numbers, length and distribution that would support specialized cellular functions. My laboratory studies the patterning of acentrosomal microtubules and its effect on cargo transport in C. elegans. We developed imaging tools and algorithms that allow an unprecedented level of analysis of microtubule organization in vivo and are compatible with live-imaging of cargo transport. We conducted unbiased screens to uncover novel microtubule regulators and are using genetics, imaging, and biochemical methods to understand their mechanisms. In parallel, we are investigating the biological significance of microtubule array patterns by examining the effects of these regulators on long-range intracellular transport. This proposal details our recent progress, including the finding of dynein regulation by an immotile kinesin at the microtubule minus-end, the identification of a protein that promotes nucleation with -tubulin, and uncovering a mechano-transduction pathway that adjusts microtubule positioning in response to stretch. For the next period we propose work that follows up on microtubule nucleation and minus-end protection, the distribution of microtubule polymers, and the regulation of cargo transport by MAPs. Given the fundamental roles of microtubules in differentiated cells, we expect this work to provide meaningful insights in the broad fields of cellular differentiation, cytoskeleton and transport. The involvement of cytoskeletal defects in numerous disorders suggests that in the long-term, our studies will help to shed light on mechanisms of cellular dysfunction that occurs during disease.