Local changes in microtubule network mobility instruct neuronal polarization and axon specification

The polarization of neurons into axons and dendrites depends on extracellular cues, intracellular signaling, cytoskeletal rearrangements, and polarized transport, but the interplay between these processes during polarization remains unresolved. Here, we show that axon specification is determined by differences in microtubule network mobility between neurites, regulated by Rho guanosine triphosphatases (GTPases) and extracellular cues. In developing neurons, retrograde microtubule flow prevents the entry of the axon-selective motor protein Kinesin-1 into most neurites. Using inducible assays to control microtubule network flow, we demonstrate that local inhibition of microtubule mobility is sufficient to guide Kinesin-1 into a specific neurite, whereas long-term global inhibition induces the formation of multiple axons. We furthermore show that extracellular mechanical cues and intracellular Rho GTPase signaling control the local differences in microtubule network flow. These results reveal a novel cytoskeletal mechanism for neuronal polarization.

Automated summary

This study reveals the importance of microtubule network mobility in the process of neuronal polarization, which is regulated by Rho GTPase signaling and extracellular cues. The differences in microtubule mobility determine the ability of Kinesin-1 to enter specific neurites, thus affecting the polarization specificity of neurons. These findings provide new insights into the cytoskeletal mechanism of neuronal polarization.