The function of the microtubule spindle during mitosis is to distribute replicated DNA equally between daughter cells. Last year Mitchison and colleagues discovered a new drug that interferes with spindle formation and they now show that this drug can be useful for the study of spindle dynamics.
Monastrol is a small, membrane-permeant compound whose action is rapidly reversible. This makes it a perfect tool for the study of mitotic spindles. Instead of targeting microtubules like many other drugs, monastrol specifically inhibits the motility of the mitotic kinesin Eg5, resulting in the formation of monopolar spindles, also called monoasters.
Kapoor et al. found that, in the presence of monastrol, centrosomes duplicate but do not separate. If the drug is added to preformed spindles in a cell-free assay, the two poles move towards each other until they merge. This confirms that Eg5 functions in centrosome separation and in the maintenance of microtubule crosslinking at the spindle midzone.
Moreover, Kapoor et al. made two interesting observations using monastrol. First, they discovered forces orthogonal to the spindle axis that had previously not been recognized. They also found that the spindle checkpoint protein Mad2 is probably sensitive to the exact number of microtubules at each kinetochore, tension at each kinetochore or the dynamic status of the kinetochore. These observations now need to be followed up.
So monastrol has been validated as a tool to study spindle dynamics, and has opened two new avenues for research.
ORIGINAL RESEARCH PAPER
Kapoor, T. M. et al. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin Eg5. J. Cell Biol. 150, 975– 988 (2000)
Mayer, T. U. et al. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971–974 ( 1999)
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Gagescu, R. Another star on drugs. Nat Rev Mol Cell Biol 1, 5 (2000). https://doi.org/10.1038/35036012