A Universal Scaling Law for Mitotic Spindles Driven by Chromosome Crowding

Size control is a universal regulatory principle in biology, ensuring that cellular structures scale precisely to maintain function and adaptability. This challenge is particularly evident in mitosis, where the mitotic spindle must be properly scaled to divide the chromosomes accurately. Failure in this process can lead to aneuploidy, a key feature of cancer and developmental disorders. 
Spindles come in all shapes and sizes, and the genomes they need to divide vary by four orders of magnitude across eukaryotes. Thus, it remains uncertain whether a universal principle exists to explain how spindles handle genomes of such wide-ranging sizes. We uncovered a universal spindle scaling law, where metaphase plate width scales with genome size following a power law with an exponent of ~1/3. Contrary to the prevailing view that spindle size is set by microtubules, motor proteins, and centrosomes, we hypothesized that chromosome crowding forces in the metaphase plate play a crucial role in shaping the spindle. Our experiments with altered chromosome number and mechanical properties in healthy and cancerous human and mouse cells, together with a theoretical model based on inter-chromosome pushing forces and mechanical manipulations of cells, confirm this hypothesis. Extending these insights across eukaryotes, we demonstrate that chromosome crowding predicts the observed power-law scaling. 
From an evolutionary perspective, the chromosome crowding model offers a mechanistic explanation for why eukaryotes with larger genomes evolved open mitosis and cell rounding during division. These adaptations help to provide more room for the spindle, which in turn prevents excessive pushing forces between chromosomes. Our finding that the spindle can adapt to larger genomes explains how polyploid cells persist during evolution to promote speciation, which is common in plants, fish, amphibians, and reptiles. In the context of cancer evolution, where many cells become polyploid or aneuploid, the spindle's adaptability to larger genomes could support the proliferation of these cells and reveal their hidden vulnerability.