Myosin-based filopodia formation

The National Institute of General Medical Sciences, part of the Department of Health and Human Services National Institutes of Health, awarded $366,517 to the Regents of the University of Minnesota on August 6, 2026, under the Biomedical Research and Research Training program (CFDA 93.859).

The award funds investigation of myosin-based mechanisms in filopodia formation. The research examines how filopodia—dynamic, actin-rich cellular projections that enable cell navigation, intercellular contact during tissue formation, and directional sensing for migration—are initiated and extended. The project focuses on the role of myosin motors in this process, using the amoeba Dictyostelium discoideum as a model system to study functional parallels with mammalian MYO10. Work includes targeted mutagenesis of conserved myosin motor regions to assess impacts on filopodia initiation and elongation, in vitro characterization of mutant motor activity, timeline analysis of initiation site assembly and forces generated during initiation, and evolutionary studies in choanoflagellates to understand how MYO10 acquired its role in filopodia formation in metazoa.

Performance takes place in Minneapolis, Minnesota, with a period of performance extending from August 6, 2026, through April 30, 2031. The assistance type is a Project Grant.

Abstract

Filopodia are dynamic, actin-rich projections that cells use to navigate complex 3D environments, make critical cell-cell contacts during tissue formation, and sense directional gradients for migration. In cancer cells, increased filopodia production is linked to invasive behavior and poor prognosis, highlighting the importance of filopodia in both normal and pathological cellular processes. The mechanism of filopodia formation remains an open question in the cytoskeletal field. A core set of conserved proteins, including a regulatory small gtpase, two regulators of actin polymerization, vasp and formin, and an MF myosin are critical. The filopodial myosins are required for initiation and extension of filopodia but their exact role is not known. The objective of the proposed work is to investigate the mechanism of MF myosin action during filopodia formation using the versatile model system, the amoeba dictyostelium (ddisc). Close functional similarity between the amoeba filopodial myosin DDMYO7 and its mammalian counterpart MYO10 means that discoveries made in ddisc will be directly relevant to mammalian MYO10. The proposed work will investigate how targeted mutations in conserved regions of the myosin motor important for coupling of atpase activity, actin binding and force generation impact filopodia initiation and elongation and the in vitro activity of mutant motors. This will provide deep mechanistic understanding of how the motor operates. A timeline of initiation site assembly and characterization of forces generated during this process will reveal further insights into how filopodia are initiated at the membrane and extend out into the environment. The project will investigate how MYO10 evolved to play a role in filopodia formation in metazoa by initiating studies in choanoflagellates, an important model system for studying the onset of multicellularity. Characterization of filopodial myosin function in evolutionarily diverse organisms will be important for defining fundamental operating principles of these important motor proteins. The proposed project will reveal how cells use a myosin-based motor to build filopodia and how core aspects of IT is motor mechanics are tuned for this function. Understanding the basic mechanism of filopodia formation has the potential to aid in the development of anti-cancer treatments.