engleski

Mitotic Spindle Chirality Provides a Passive Mechanical Response to Forces and Depends on Microtubule Motors and Crosslinkers

Mechanical forces produced by motor proteins and microtubule dynamics within the mitotic spindle are crucial for the movement of chromosomes and their segregation into the emerging daughter cells. In addition to linear forces, rotational forces or torques are present in the spindle, reflected in the left-handed twisted shapes of microtubule bundles that make the spindle chiral. However, the biological role and molecular origins of spindle chirality are unknown. By developing methods to measure spindle twist, we show that spindles have highest twist values at the beginning of anaphase. To test whether the spindle reacts to an external force by changing the twist, we compressed the spindles along its long axis, which indeed resulted in stronger left-handed twist. Inhibition or depletion of motor proteins that perform chiral stepping, Eg5/kinesin-5 or Kif18A/kinesin-8, decreased the twist, suggesting that these motors regulate twist by rotating microtubules around one another within the bridging fibers or at the spindle pole. Depletion of the microtubule crosslinker PRC1 and the nucleator augmin decreased the left-handed twist or even caused right-handed twist, which indicates that PRC1 contributes to the twist by constraining free rotation of microtubules within the bridging fibers, and augmin by nucleating bridging microtubules. Overall, round spindles were more twisted than elongated ones, implying a correlation between bending moments and twist. In conclusion, spindle twist is largely dependent on the shape of the spindle and controlled by molecular activities within the bridging fibers and at the spindle poles. We propose a physiological role for spindle chirality in providing a passive mechanical response to forces, decreasing the risk of spindle breakage under high load.

Mitotic spindle ; Mitosis ; Chirality ; Twist ; Torques ; Rotation ; Motor proteins ; Kinesins ; Augmin ; Spindle compression

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