Myosin-X and the molecular basis of filopodia function

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DESCRIPTION (provided by applicant): Filopodia are slender cellular extensions that appear to function as cellular sensors that allow cells to interact with their surroundings in processes such as nerve growth, blood vessel formation, and the metastasis of cancer cells. Despite the central importance of filopodia and related structures such as microvilli and stereocilia, the molecular mechanisms that regulate the formation and function of these structures remain unclear. Growing evidence indicates that the MyTH4-FERM myosins, a newly recognized family of unconventional myosins, have critical roles as motor proteins that function in filopodia and related structures. Humans express four MyTH4-FERM myosins and mutations in two of these lead to hereditary deafness. We have discovered that myosin-X, a vertebrate-specific member of the MyTH4-FERM myosins that localizes to the tips of filopodia, is a remarkably potent inducer of filopodia, and undergoes a novel form of motility within filopodia. This has led us to hypothesize that myosin-X functions as a motor for a previously unsuspected system of intracellular transport within filopodia and related structures. We thus propose to: 1) Determine the molecular mechanisms by which myosin-X induces filopodia. 2) Investigate the basic properties of the novel system of intrafilopodial motility we have discovered. 3) Isolate full-length myosin-X and determine its fundamental biochemical properties 4) Determine the cellular and organismal functions of myosin-X using a mouse knock-out. By investigating myosin-X, the MyTH4-FERM myosin that is expressed in most vertebrate cells and tissues, this research will provide a model to investigate the fundamental cell biology of the MyTH4-FERM myosins and their roles in filopodia-like structures. This research is particularly relevant to deafness, since hearing depends on stereocilia, filopodia-like mechanosensors that contain a core of actin filaments. In addition, mutations in at least five other unconventional myosins are already known to cause human deafness, including Usher syndrome 1b, the leading cause of hereditary deaf-blindness. There is also growing evidence that filopodia can act as cellular highways that transport materials such as key signaling molecules and viruses, so studies of myosin-X function in filopodia will contribute to our understanding of the fundamental cell biology underlying nerve regeneration, angiogenesis, and the spread of cancer cells.