Growth Cone Motility and Guidance

Tuesday, June 17, 2003 - 1:00pm - 2:00pm
Lind 409
Kathryn Tosney (University of Michigan)
The growth cone is the pathfinding organ of the neuron. It is the motile tip of the neuronal axon. It extends cellular processes, filopodia (dynamic cellular extensions containing actin bundles), that are essential for the axon to navigate to its proper destination. Little is known about the dynamics or signaling mechanisms, although a first step in initiating signal cascades is often filopodial adhesion. In contrast to the general assumption that all cell-substrate adhesions play equivalent roles, our studies establish that adhesions made by individual filopodia can mediate different and distinctive functions. The roles of filopodia and their adhesions in motility and guidance will be reviewed in this talk.

Adhesions at three sites in individual filopodia were found to have dissimilar functions. Tip adhesions suffice to signal. Adhesions made by single filopodial tips can initiate signal cascades that systematically alter cytoskeletal dynamics. Alterations are discrete, robust, and suffice to mediate specific growth cone turning behaviors. Basal adhesions form at nascent filopodial bases before filopodia emerge, remain at bases throughout filopodial lifetimes, and function in filopodial emergence and dynamics. They specifically associate with focal rings, newly described organelles that link actin bundles to the basal adhesion and thereby mediate substrate anchorage. Focal rings also develop in Schwann cells and other cell types. Shaft adhesions lie along filopodial shafts, lack focal rings, and control the extent of lamellar (veil) advance. Shaft adhesions inhibit veil advance. Veils are unaffected by basal adhesions, but readily advance along filopodia until they encounter shaft adhesions, where they stop advancing. Most intriguing, navigational cues can guide by targeting shaft adhesions. Filopodial tip adhesion to an inhibitory cue induces shaft adhesions and abolishes veil advance, whereas tip adhesion to a permissive cue prohibits shaft adhesions and promotes veil advance. Shaft adhesions can thus regulate both motility and navigation. The discovery of functionally distinctive adhesions compels a reevaluation of signaling mechanisms that were previously inferred under the assumption that adhesions are mono-functional. The discovery also shows that guidance responses are much more discrete and invariant than previously supposed, and are thus good candidates for mathematical modeling. Support: NSF-0212326.

Recent, relevant papers:

Steketee M., K.W. Tosney. (1999). Contact with isolated sclerotome cells steers sensory growth cones by altering distinct elements of extension. J. Neurosci. 19: 3495-3506

Polinsky, M., K. Balazovich and K.W. Tosney (2000). Identification of an invariant response: Contact with Schwann cells induces veil extension in growth cones. J. Neurosci. 20: 1044-1055.

Steketee, M., K.J. Balazovich and K.W. Tosney (2001). Filopodial initiation and a novel filament-organizing center, the focal ring. Mol. Biol. Cell. 12: 2378-2395.

Steketee and Tosney (2002) Three functionally distinct adhesions in filopodia: Shaft adhesions control lamellar extension. J. Neurosci. 22:8071-8083.