Can Molecular Motors Drive Distance Measurements in Injured Neurons?

Injury to nerve axons induces diverse responses in neuronal cell bodies, some of which are influenced by the distance from the site of injury. This suggests that neurons have the capacity to estimate the distance of the injury site from their cell body. Recent work has shown that the molecular motor dynein transports importin-mediated retrograde signaling complexes from axonal lesion sites to cell bodies, raising the question whether dynein-based mechanisms enable axonal distance estimations in injured neurons? We used computer simulations to examine mechanisms that may provide nerve cells with dynein-dependent distance assessment capabilities. A multiple-signals model was postulated based on the time delay between the arrival of two or more signals produced at the site of injury–a rapid signal carried by action potentials or similar mechanisms and slower signals carried by dynein. The time delay between the arrivals of these two types of signals should reflect the distance traversed, and simulations of this model show that it can indeed provide a basis for distance measurements in the context of nerve injuries. The analyses indicate that the suggested mechanism can allow nerve cells to discriminate between distances differing by 10% or more of their total axon length, and suggest that dynein-based retrograde signaling in neurons can be utilized for this purpose over different scales of nerves and organisms. Moreover, such a mechanism might also function in synapse to nucleus signaling in uninjured neurons. This could potentially allow a neuron to dynamically sense the relative lengths of its processes on an ongoing basis, enabling appropriate metabolic output from cell body to processes.Author Summary: Neurons have extremely long axonal processes that can reach lengths of up to 1 meter in human peripheral nerves. The neuronal cell body response to nerve injury is dependent on signals carried by molecular motors from the lesion site in the axon. The distance between the injury site and the cell body influences the type of response, suggesting that neurons must be able to estimate the distance of an axonal injury site, although how they do this is unknown. We have used a computational approach to model intracellular distance measurement after nerve injury. The models show the feasibility of a mechanism based on a rapid, near instantaneous, signal carried by action potentials in the nerve, followed by multiple slower signals carried on molecular motors. Such a mechanism can enable a neuron to discriminate between distances as close as 10% of total axon length. The model provides insights on retrograde injury signaling in neurons, including the biological relevance of the mechanism over different scales of nerves and organisms. Moreover, if similar mechanisms function in synapse to nucleus signaling in uninjured neurons, this could enable estimation of relative process lengths, thus guiding metabolic output from cell bodies to axons.