Stabilization of Migration Polarity by Microtubules

Zhang et al. , Proc. Natl. Acad. Sci. USA 111:16383-16388 (2014)

Establishment of migration polarity requires the formation of distinct regions of front and rear, which in turn involves coordination over the cell length.  We have shown with computer modeling that such coordination may be achieved with a Local Excitation Global Inhibition (LEGI) mechanism, which was first proposed to explain chemotaxis.  In this study, we suggest that the microtubules, through their omni-presence in the cytoplasm and functions for intracellular transport, are involved in the global distribution of inhibitory signals.

Disassembly of Microtubules Induces Ocillatory Movement

RPE-1 cell, when cultured on narrow strips of gelatin, migrate persistently (top).  Upon treatment with nocodazole to disassemble microtubules (middle), or ciliobrevin D to inhibit the microtubule motor dynein (bottom), persistent migration turns into oscillations.  The effect may be understood as the inhibition of global transport of inhibitory signals away from the front, which causes these signals to accumulate at the front and create negative feedbacks to limit the duration of protrusive activities.

Disassembly of Microtubules Induces Ocillatory Movement

Oscillation of a RPE-1 cell expressing RFP-zyxin, which concentrates at the tail to serve as a tail marker, induced by the treatment with nocodazole to disassemble microtubules.  Phase contrast images show striking alternative protrusive activies at the two ends (bottom), while fluorescence images show alternative concentrations of RFP-zyxin at the opposite end (top).

Inhibition of Myosin II Slows Down Nocodazole-Induded Oscillations

Recapitulation of Nocodazole-Induced Oscillations by Modeling

Persistent migration of control cells may be recapitulated, in the first part of the video, by implementing the LEGI mechanism in a computer model.  The display field is moved repeatedly to bring the model cell back to the center while the cell continues to move downward.  The second part of the video simulates the effect of nocodazole by preventing the inhibitory signals from spreading globally, which causes persistent migration to turn into oscillations.  Color represents the net magnitude of signals, which may be positive to stimulate protrusion or negative to stimulate retraction.

Modeling of Nocodazole-Induced Oscillation at Steady State

Recapitulation of Blebbistatin-Induced Increase in Oscillation Period

increase in oscillation period upon the inhibition of myosin II by blebbistatin is recapitulated by delaying the generation of inhibitory signals following the switch in direction.  

Modeling the Effect of Cell Length on Nocodazole-Induced Oscillation

Side by side simulation of a short cell and a long cell treated with nocodazole under identical conditions, showing an increase in oscillation period with cell length.