Abstract
In the developing nervous system, axons are guided to their synaptic targets by motile structures at the axon tip called growth cones, which reorganize their cytoskeleton in order to steer in response to chemotactic cues. Growth cone motility is mediated by an actin-adhesion “clutch” mechanism, in which mechanical attachment to a substrate, coupled with polarized actin growth, produces leading-edge protrusion. Several studies suggest that dynamic microtubules (MTs) in the growth cone periphery play an essential role in growth cone steering. It is not yet well-understood how the MT cytoskeleton and the dynamic actin-adhesion clutch system are coordinated to promote growth cone navigation. I introduce an experimentally motivated stochastic model of the dynamic reorganization of the growth cone cytoskeleton in response to external guidance cues. According to this model, asymmetric decoupling of MTs from actin retrograde flow leads to a local influx of MTs to the growth cone leading edge, and the leading-edge MT accumulation is amplified by positive feedback between MTs and the actin-adhesion clutch system. Local accumulation of MTs at the leading edge is hypothesized to increase actin adhesion to the substrate, which attenuates actin retrograde flow and promotes leading-edge protrusion. Growth cone alignment with the chemotactic gradient is predicted to be most effective for intermediate levels of sensitivity of the adhesion strength to the presence of leading-edge MTs. Quantitative predictions of the MT distribution and the local rate of retrograde actin flow will allow the hypothetical positive feedback mechanism to be experimentally tested.
Highlights
Specialized sensory-motile structures called growth cones at the tips of growing axons lead neuronal pathfinding during nervous system development
When the retrograde flow speed matches the rate of leading edge polymerization, a condition known as “treadmilling,” the continual turnover of actin in the absence of leading-edge protrusion can be likened to a vehicle with an unengaged clutch, expending energy without driving growth cone motility (Mitchison and Kirschner, 1988; Lin and Forscher, 1995; Jay, 2000; Bard et al, 2008)
I hypothesize that growth cone steering is coordinated through a positive feedback mechanism in which an attractive guidance cue decreases the coupling of MTs to actin retrograde flow, allowing MTs to invade the periphery of the growth cone
Summary
Specialized sensory-motile structures called growth cones at the tips of growing axons lead neuronal pathfinding during nervous system development. I hypothesize that growth cone steering is coordinated through a positive feedback mechanism in which an attractive guidance cue decreases the coupling of MTs to actin retrograde flow, allowing MTs to invade the periphery of the growth cone.
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