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.
Highlights
Cell biology seeks to understand how nanometer-scale molecules organize micron-scale cells, a question well-suited to theory and modeling (Marshall, 2017)
To better understand the key mechanistic requirements for chromosome biorientation and how kinetochore number and attachment affect spindle length stability, we developed a computational model of fission-yeast mitosis
To understand the mechanisms most important for proper chromosome alignment on the spindle, we developed a computational model of fission-yeast mitosis (Figure 1) that includes spindle
Summary
Cell biology seeks to understand how nanometer-scale molecules organize micron-scale cells, a question well-suited to theory and modeling (Marshall, 2017). Chromosome segregation in eukaryotes is performed by the mitotic spindle, a self-organized microtubule (MT)-based machine (Bray, 2000; McIntosh et al, 2012). Dynamic spindle MTs are typically organized with their plus-ends toward the center of the spindle, forming a bipolar array as the spindle poles move apart (Figure 1; Taylor, 1959; McIntosh et al, 2012). MTs attach to duplicated chromosomes at kinetochores and align them at the spindle midzone (Figure 1A–C; Musacchio and Desai, 2017; Hinshaw and Harrison, 2018; Hamilton et al, 2019).
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