Molodtsov group discover novel physical principles underlying assembly of bipolar mitotic spindles

As cells go into cell division, sister chromatids are segregated into the two newly formed cells with extraordinary accuracy to ensure that genomes are correctly passed onto future generations of cells.

To achieve this, cells assemble a specialized machine made of microtubule filaments whose function is to segregate chromosomes – the mitotic spindle. The size and position of the spindle are important: displaced and misorganized spindles lead to chromosome segregation errors and aneuploidy, which is hallmark of cancer.

To build the spindle, cells move microtubule organization centres from one part of the cell to both parts of the cell converting monopolar organization of microtubules into bipolar spindle. The widely accepted view of this process is that the forces generated by molecules that push poles apart are equilibrated by the forces that pulls them back in and the emerging balance of forces determines the size of the spindle.

However, how forces generated by individual motors integrate together is unknown and neither computer simulations nor experiments could explain how combinations of molecules acting in the antiparallel overlaps can produce stable bipolar organization from the initial monopolar configuration.

To address these questions, Lee-Ya Chu, postdoctoral researcher in Molodtsov’s group, designed an artificial spindle assay in which she mimicked spindle poles by two optical trapped beads with microtubule nucleation centres on them. This allowed her to add various molecules that bind microtubules and measure the resulting forces.

Lee-Ya discovered that special complexes at microtubule tips act as force generators that contribute to the force balance in mitotic spindles. Because these forces are generated at the tips their contribution is unique and on its own can generate stable bipolar organization.

“By developing new tools to measure mechanical contributions of individual molecules to the force balance in mitotic spindle, we are one step ahead in generating the map of mechanical forces that assemble and maintain mitotic spindles and move chromosomes,” explained Maxim Molodtsov, Associated Professor at the Department of Physics and Astronomy and group leader at the Francis Crick Institute who led the study. “It is known that targeting forces in spindles may preferentially target cancer cells while sparing normal human tissue. Our research opens up new ways to directly measure contributions of various molecules in the mechanical force balance in mitotic spindle and potentially identify best candidates for targeting this balance.”

The work was supported by the Francis Crick Institute, which receives funding from the UK Medical Research Council, Cancer Research UK and the Wellcome Trust.

Links

• Research article in Nature Communications
• Dr. Maxim Molodtsov's academic profile
• UCL Physics & Astronomy  
• UCL Institute for the Physics of Living Systems