"The megadalton cytoplasmic dynein complex, whose motor subunit is encoded by a single gene, provides the major microtubule minus end-directed motility in cells and is essential for a wide range of processes, ranging from the transport of proteins, RNA, and membrane vesicles to nuclear migration and cell division. To achieve this stunning functional diversity, cytoplasmic dynein is subject to tight regulation by co-factors that modulate localization, interaction with cargo, and motor activity. At present, our knowledge of the underlying mechanisms remains limited. An overarching goal of this proposal is to gain an understanding of how interactions with diverse adaptor proteins regulate dynein function in space and time. We choose the nematode C. elegans as our model system, because it will enable us to study the biology of dynein regulation in the broad context of a metazoan organism. The nematode’s versatile genetic tools, its biochemical tractability, and the powerful molecular replacement technologies available, this makes for a uniquely attractive experimental system to address the mechanisms employed by dynein regulators through a combination of biochemical, proteomic, and cell biological assays. Specifically, we propose to use a biochemical reconstitution approach to obtain a detailed molecular picture of how dynein is targeted to the mitotic kinetochore; we will perform a forward genetic and proteomic screen to expand the so-far limited inventory of metazoan dynein interactors, whose functional characterization will shed light on known dynein-dependent processes and lead to novel unanticipated lines of research into dynein regulation; we will dissect the function and regulation of the most important dynein co-factor, the multi-subunit dynactin complex; and finally we will strive to establish a novel C. elegans model for human neurodegenerative disease, based on pathogenic point mutations in a dynactin subunit."