Kathryn W. Tosney

    Growth Cone Motility


Cell motility plays a central role in both normal and disease processes, including development, wound healing, inflammation and metastasis. Cell movement requires highly dynamic rearrangements of the actin filament network, and the extension of two types of cellular processes that have dramatically different physical and molecular organizations. Lamellipodia are thin, peripheral sheets of actin-rich cytoplasm that extend through fairly well characterized molecular interactions. Filopodia are cylindrical projections containing filament bundles, and their dynamics are less well understood.

In neurons, the importance of filopodia is particularly clear. Without filopodia, a growth cone can still advance but it can no longer navigate properly. Filopodia are required both as sensory structures, and as effectors of motility. They receive signals from the molecular environment and transmit signals that alter the cytoskeleton and cellular motility.

Neurons have advantages for studying the interplay between filopodial and lamellar extension. Growth cones at the tip of actively extending axons harbor virtually all the protrusive activity. Growth cones have a central region filled with cytoplasm and prominent microtubules, and a peripheral lamellar region that contains less cytoplasm and is therefore thinner and nicely optically accessible. Moreover, in growth cones the portions of such lamellae that are actively extending are easily detected. They advance as thin "veils" between supporting filopodia. Filopodia can extend simultaneously with the veils, giving a distinctly "lamellar" appearance. Activities at the prospective filopodia tip assure that actin nucleates and elongates to form long straight filaments (rather than the short branched filaments typical of veils).

Our work has shown that activities at the prospective filopodial base are also essential. At the earliest stage in filopodial emergence, an adhesion develops that will remain at the filopodial base (the "basal adhesion"). At this adhesion, novel organelle develops, the "Focal Ring". The focal ring is closely associated with the basal adhesion (but not with other adhesions), radiates its own actin filaments with 12-fold symmetry. These filaments are encorporated into the filopodium during bundling of filaments that emerge from the filopodial tip. This encorporation links the filapodial bundle to the adhesion via the focal ring, and thereby supplies the substratum anchorage essential for filopodial emergence and elongation.

Discovery of the Focal Ring opens exciting new persepectives for understanding filopodial motility. The Focal Ring Model interfaces with the current Convergent Elongation Model of Svitkina et al (2003), which deals with events at the prospective filopodial tip, in which filaments converge at the nascent filopodial tip, and then elongate and bundle to form the filopodial shaft. The Focal Ring Model elucidates complimentary events at the prospective base that are essential for filopodial extension.. As the filaments bundle, they physically incorporate filaments that are extending from and anchored in the focal ring. Without this firm anchorage, the actin polymerzation cannot drive filopodial protrusion; instend, the elongating filaments merely disapate into the internal cytoplasm.

ring model