Growth Cone Turning Induced by Direct Local Modification of Microtubule Dynamics

Abstract

Pathfinding by nerve growth cones depends on attractive and repulsive turning in response to a variety of guidance cues. Here we present direct evidence to demonstrate an essential and instructive role for microtubules (MTs) in growth cone steering. First, both growth cone attraction and repulsion induced by diffusible cues in culture can be completely blocked by low concentrations of drugs that specifically inhibit dynamic microtubule ends in the growth cone. Second, direct focal photoactivated release of the microtubule-stabilizing drug taxol on one side of the growth cone consistently induces attraction (turning toward the site of application). Using the focal pipette application method, we also show that local MT stabilization by taxol induces growth cone attraction, whereas local MT destabilization by the microtubule-disrupting drug nocodazole induces repulsion (turning away). Finally, the microtubule-initiated attractive turning requires the participation of the actin cytoskeleton: local microtubule stabilization induces preferential protrusion of lamellipodia before the attractive turning, and the attraction can be abolished by inhibition of either actin polymerization or the Rho family GTPases. Together, these results demonstrate a novel steering mechanism for growth cones in which local and selective modification of dynamic microtubules can initiate and instruct directional steering. With the subsequent concerted activity of the actin cytoskeleton, this microtubule-initiated mechanism provides the growth cone with the additional means to efficiently navigate through its environment.

Collapsin Response Mediator Protein 4 Regulates Growth Cone Dynamics through the Actin and Microtubule Cytoskeleton

“…CRMP4 Regulates Actin and Microtubule Dynamics-Microtubule and actin dynamics must be intricately coordinated in growth cones to mediate axon extension and turning (51,52). CRMP4 distribution is strongest in the microtubule-rich central region of the growth cone, consistent with its ability to regulate microtubule dynamics.…”

Asymmetric redistribution of GABA receptors during GABA gradient sensing by nerve growth cones analyzed by single quantum dot imaging

“…Pharmacological treatments provided additional information on the mechanisms controlling the distribution of GABA A Rs. We tested the role of MTs, which play a crucial role in axon growth and in directional sensing mechanisms (10,20) and interact, at least indirectly, with GABA A Rs (21,22). We found that the asymmetric redistribution of the receptors was suppressed when MTs were depolymerized with nocodazole (Fig.…”

The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development

“…The activity-regulated localization of FMRP into dendrites and spines (36) further implicates the possibility for FMRP to regulate translation of MAP1B and microtubule dynamics within the individual dendrite and͞or synapse, perhaps in response to neurotransmitter release. Considering the critical roles of microtubule dynamics in the development of neuronal networks, particularly in growth cone dynamics and synapse formation (32,(37)(38)(39)(40), abnormal microtubule dynamics caused by FMRP deficiency provides a conceivable mechanism underlying the abnormalities in structural synaptic plasticity in fragile X mental retardation, represented by the delayed dendritic spine maturation in vivo (6) and the deficits in synapse formation in primary cultured neurons (41).…”