Filopodia are finger-like cellular protrusions hypothesized to act as sensors that allow cells to contact and interact with their environment. Filopodia are known or hypothesized to have key roles in processes such as nerve growth, angiogenesis, wound healing, and hearing. Structurally related protrusions known as stereocilia function as mechanosensors responsible for our senses of hearing and balance, and defects in the assembly of stereocilia, or in the unconventional myosins that localize to them, cause many forms of human deafness. Although the tips of filopodia, microvilli, and stereocilia all contain a specialized structure known as the tip complex, remarkably little is known about the basic properties of the tip complex, even though it clearly represents a key site of cell contact and interaction that is also important in the formation of these protrusions. Our discovery that myosin-X (Myo10) localizes to the tips of filopodia and binds to ?-integrins has led us to hypothesize that Myo10 is a central component of the filopodial tip complex, and that the tip complex is a specialized site of polymerization, adhesion, and signaling. Since very little is known about the filopodial tip complex, especially in comparison to intensively studied adhesive structures such as focal adhesions, our objective is to determine the basic properties of the filopodial tip complex and define its roles in filopodial adhesion and signaling.
Our specific aims are to: 1) Determine the composition and properties of the filopodial tip complex. 2) Visualize the formation and dynamics of the tip complex and investigate its role in cell signaling. 3) Determine the functions of the filopodial tip complex in adhesion and mechanotransduction. By defining the basic properties of the filopodial tip complex, this research will provide fundamental information needed to understand key cell biological processes underlying human health and disease. In addition, studies of Myo10 and the filopodial tip complex provide a model system for understanding the functions of unconventional myosins in stereocilia and other structures based on actin bundles.

Public Health Relevance

The proposed research is relevant to public health because it investigates the molecular mechanisms by which finger-like cellular protrusions known as filopodia interact with their surroundings, a process that is critical for neural development, angiogenesis, and cancer metastasis. This research also provides an important model system for understanding the roles of myosins in hearing and human deafness. This research will thus fill critical gaps in our knowledge of the fundamental cell biological processes that underlie majo human diseases.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Freeman, Nancy
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Purcell, Erin B; McKee, Robert W; Courson, David S et al. (2017) A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production during Stationary Phase. Infect Immun 85:
Courson, David S; Cheney, Richard E (2015) Myosin-X and disease. Exp Cell Res 334:10-5
Bultema, Jarred J; Boyle, Judith A; Malenke, Parker B et al. (2014) Myosin vc interacts with Rab32 and Rab38 proteins and works in the biogenesis and secretion of melanosomes. J Biol Chem 289:33513-28
Lin, Lin; Sun, Wei; Throesch, Ben et al. (2013) DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development. Nat Commun 4:2270
Lin, Wan-Hsin; Hurley, Joshua T; Raines, Alexander N et al. (2013) Myosin X and its motorless isoform differentially modulate dendritic spine development by regulating trafficking and retention of vasodilator-stimulated phosphoprotein. J Cell Sci 126:4756-68
Bishai, Ellen A; Sidhu, Gurjit S; Li, Wei et al. (2013) Myosin-X facilitates Shigella-induced membrane protrusions and cell-to-cell spread. Cell Microbiol 15:353-367
Raines, Alexander N; Nagdas, Sarbajeet; Kerber, Michael L et al. (2012) Headless Myo10 is a negative regulator of full-length Myo10 and inhibits axon outgrowth in cortical neurons. J Biol Chem 287:24873-83
Liu, Katy C; Jacobs, Damon T; Dunn, Brian D et al. (2012) Myosin-X functions in polarized epithelial cells. Mol Biol Cell 23:1675-87
Kerber, Michael L; Cheney, Richard E (2011) Myosin-X: a MyTH-FERM myosin at the tips of filopodia. J Cell Sci 124:3733-41
McMichael, Brooke K; Cheney, Richard E; Lee, Beth S (2010) Myosin X regulates sealing zone patterning in osteoclasts through linkage of podosomes and microtubules. J Biol Chem 285:9506-15

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