Mechanisms of chromosome biorientation and bipolar spindle assembly analyzed by computational modeling

Abstract

The essential functions required for mitotic spindle assembly and chromosome biorientation and segregation are not fully understood, despite extensive study. To illuminate the combinations of ingredients most important to align and segregate chromosomes and simultaneously assemble a bipolar spindle, we developed a computational model of fission-yeast mitosis. Robust chromosome biorientation requires progressive restriction of attachment geometry, destabilization of misaligned attachments, and attachment force dependence. Large spindle length fluctuations can occur when the kinetochore-microtubule attachment lifetime is long. The primary spindle force generators are kinesin-5 motors and crosslinkers in early mitosis, while interkinetochore stretch becomes important after biorientation. The same mechanisms that contribute to persistent biorientation lead to segregation of chromosomes to the poles after anaphase onset. This model therefore provides a framework to interrogate key requirements for robust chromosome biorientation, spindle length regulation, and force generation in the spindle.

Comparison of mechanisms of kinetochore capture with varying number of spindle microtubules

“…A second motivation is related to the spindle assembly in fission yeast [6,8,[40][41][42][43][44], and more specifically, to an experiment [8] which reported an exception to the usual S&C mechanism in Schizosaccharomyces pombe (fission yeast). Here a diffusing KC inside the nucleus is captured by MTs executing rotational diffusion (RD) [8,40,42], being pivoted at the spindle pole body (SPB) [see Figs.…”

How Essential Kinesin-5 Becomes Non-Essential: Force Balance and Microtubule Dynamics Matter

“…Ase1 and Cls1/Peg1 bundle and stabilise antiparallel spindle microtubules (Figure 4). Notably, theoretical modelling supports bipolar spindle assembly by these two factors; Brownian dynamics-kinetic Monte Carlo simulations show that Ase1 and Cls1/Peg1 activity are sufficient for initial bipolar spindle formation [57,70,71]. Unlike in other species, C. elegans does not require Kinesin-5/BMK-1 for bipolar spindle formation [72].…”

Modeling reveals cortical dynein-dependent fluctuations in bipolar spindle length

“…Many models have been developed to understand early centrosome separation and spindle formation [8,9,10,11,12,13,14,15], chromosome dynamics, [16,17,18,19,20,21], and spindle elongation during anaphase [22,23,24]. Since the exact spatiotemporal motor force generation is not known, computational force-balance models have been used to understand key mechanistic components that modulate positioning of spindle poles and bipolar spindle formation [25,26,27,13,28].…”

“…Due to the large number of motor interactions [29,6,30], computational models generally simplify dynamics and focus on the role of a limited number of MT-motor interactions. Additionally, since many modeling studies and experimental parameters are based on those of embryos or yeast [31,18,10,32], biological interpretation and application to mammalian cells, with a more complex spindle and genome, is challenging.…”