Model for Microtubule-Actin Interactions in Growth Cone Motility

Abstract

A growth cone is a motile structure on the tips of axons that guides axon extension to synaptic targets during nervous system development. In order to translate chemotactic signals into a mechanical response, the microtubule and actin filaments in the growth cone self-organize into a motile lamellipodial structure. A meshwork of actin filaments in the lamellipodium are continually transported inward by myosin-driven forces, at a speed that matches actin polymerization at the leading edge. This creates a stationary actin treadmill when actin adhesion to the substrate is low, and allows leading edge protrusion when actin adhesion increases in response to guidance cues. A population of highly dynamic microtubules that explore the P domain in stochastic bursts of growth and shrinking have also been shown to play an essential role in growth cone steering. Cooperation between these two filament systems is known to be essential for directed motility. We present initial results from a theoretical model of the growth cone cytoskeleton in the lamellipodium, testing the hypothesis that dynamic microtubules and actin work cooperatively to guide growth cone motility. We simulate dynamically unstable microtubules that transiently attach to actin retrograde flow, actin-myosin-adhesion force balance, and test several scenarios for feedback between microtubules and actin. Our theoretical work is guided by direct visualization of actin and microtubule dynamics during growth cone advance with fluorescent speckle microscopy.