The motility of olfactory ensheathing cells: a hitchhiker's guide to olfactory axon migration

During development and during regeneration in the adult, olfactory ensheathing cells (OECs) are intimately associated with axons of olfactory sensory neurons along their entire trajectory. It is assumed that OECs are essential for axon growth but little is known about how OECs and axons interact and respond to each other. We hypothesised that the motility of OECs directs the migration of olfactory axons. To address this we used timelapse imaging of fluorescently labelled primary cultures of olfactory sensory neurons and OECs to determine the mechanisms of olfactory axon extension and OEC interactions. We reveal here for the first time that the extension of pioneer olfactory axons is largely dependent on the motility of the underlying OECs. This intimate association is in part initiated and mediated by lamellipodial waves along the shaft of OEC processes. Moreover, as axons remain adhered to axons at all times, perturbation of OEC movement via GDNF and inhibitors of the JNK and SRC kinases significantly altered axon motility (n=20). We also reveal that inhibition of NCAM significantly disrupted OEC cell-cell recognition (n=10) resulting in increased OEC migration, while OEC-axon adhesion was maintained. Laser ablation of OECs, or substitution of OECs by Schwann cells, inhibited axon outgrowth. These results demonstrate that olfactory sensory axon outgrowth is dependent on cell-cell contact with OECs. Rather than merely providing support for axon growth the glia of the olfactory system strongly regulate the migration of olfactory axons.