期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：16383-16388
DOI：10.1073/pnas.1410533111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceWe discovered that cells on micropatterned strips change from highly persistent migration into striking oscillations upon the disassembly of microtubules. The oscillation phenomenon then allowed us to apply computer modeling to understand how the positive feedback in the local-excitation-global-inhibition (LEGI) mechanism, responsible for the persistence of migration, might be converted into negative feedback to drive oscillations upon the disassembly of microtubules. Our analyses led to the conclusion that microtubules facilitate the transport of inhibitory signals and their global distribution. Depending on the relative position of excitation and inhibitory signals, the resulting feedback in the integrated control circuit may be either positive or negative. Our finding therefore provides important insights into the role of microtubules in the control circuit of cell migration. Microtubules are known to play an important role in cell polarity; however, the mechanism remains unclear. Using cells migrating persistently on micropatterned strips, we found that depolymerization of microtubules caused cells to change from persistent to oscillatory migration. Mathematical modeling in the context of a local-excitation-global-inhibition control mechanism indicated that this mechanism can account for microtubule-dependent oscillation, assuming that microtubules remove inhibitory signals from the front after a delayed generation. Experiments further supported model predictions that the period of oscillation positively correlates with cell length and that oscillation may be induced by inhibiting retrograde motors. We suggest that microtubules are required not for the generation but for the maintenance of cell polarity, by mediating the global distribution of inhibitory signals. Disassembly of microtubules induces cell oscillation by allowing inhibitory signals to accumulate at the front, which stops frontal protrusion and allows the polarity to reverse.
