Force Generation by Molecular-Motor-Powered Microtubule Bundles; Implications for Neuronal Polarization and Growth

摘要

The heavily cross-linked microtubule (MT) bundles found in neuronal processes play a central role in the initiation, growth and maturation of axons and dendrites; however, a quantitative understanding of their mechanical function is still lacking. We here developed computer simulations to investigate the dynamics of force generation in 1D bundles of MTs that are cross-linked and powered by molecular motors. The motion of filaments and the forces they exert are investigated as a function of the motor type (unipolar or bipolar), MT density and length, applied load, and motor connectivity. We demonstrate that only unipolar motors (e.g., kinesin-1) can provide the driving force for bundle expansion, while bipolar motors (e.g., kinesin-5) oppose it. The force generation capacity of the bundles is shown to depend sharply on the fraction of unipolar motors due to a percolation transition that must occur in the bundle. Scaling laws between bundle length, force, MT length and motor fraction are presented. In addition, we investigate the dynamics of growth in the presence of a constant influx of MTs. Beyond a short equilibration period, the bundles grow linearly in time. In this growth regime, the bundle extends as one mass forward with most filaments sliding with the growth velocity. The growth velocity is shown to be dictated by the inward flux of MTs, to inversely scale with the load and to be independent of the free velocity of the motors. These findings provide important molecular-level insights into the mechanical function of the MT cytoskeleton in normal axon growth and regeneration after injury.