Stoichiometric interactions explain spindle dynamics and scaling across 100 million years of nematode evolution

Abstract

The spindle shows remarkable diversity, and changes in an integrated fashion, as cells vary over evolution. Here, we provide a mechanistic explanation for variations in the first mitotic spindle in nematodes. We used a combination of quantitative genetics and biophysics to rule out broad classes of models of the regulation of spindle length and dynamics, and to establish the importance of a balance of cortical pulling forces acting in different directions. These experiments led us to construct a model of cortical pulling forces in which the stoichiometric interactions of microtubules and force generators (each force generator can bind only one microtubule), is key to explaining the dynamics of spindle positioning and elongation, and spindle final length and scaling with cell size. This model accounts for variations in all the spindle traits we studied here, both within species and across nematode species spanning over 100 million years of evolution.

Mechanical Mechanisms of Chromosome Segregation

“…In another series of studies, a combination of evolutionary genetics and biophysics was used to investigate spindle length and the elongation of the spindle in anaphase in the first mitotic division in nematodes [ 43 , 125 , 126 ]. The evolutionary genetics aspect revealed that selection acts predominantly on the size of cells, and only indirectly influences the spindle through its scaling with cell size.…”

“…Some researchers favor models in which pulling forces stably position the spindle, while others favor models where pulling forces are destabilizing and pushing forces are stabilizing. Disagreement on this point even exists regarding the nature of forces acting on the first mitotic spindle in Caenorhabditis elegans ( C. elegans ) embryos [ 43 , 44 ], which is arguably the system where this issue has been most thoroughly studied. In addition to their role in spindle positioning, extensive evidence in diverse systems also shows that pulling forces from astral microtubules drives spindle elongation [ 16 ].…”

“…The contribution of these forces has also been most intensely studied in the first mitotic division of C. elegans . In that system, the spindle poles are stably positioned by forces exerted from astral microtubules, both before the start of spindle elongation and after spindle elongation has ceased [ 43 , 44 ]. Thus, spindle elongation in C. elegans entails the poles switching from one initially stable position to a second, final stable position.…”

“…A very simple possibility is that when the spindle is stably positioned with a constant length, each pole is stationary because the astral force acting on it is balanced by the tension in the spindle (though such a description is not always appropriate [ 43 ]). In this case, if one of the poles were disconnected from the rest of the spindle (by a laser ablation experiment, for example), the astral force on the pole would no longer be balanced by tension in the spindle [ 46 ].…”

Cell division geometries as central organizers of early embryo development

“…As described more than 150 years ago in Hertwig's rules, many zygotes and blastomeres divide in their middle and orthogonal to their long shape axis 7 . Shape sensing is now known to be regulated in large part by mechanisms that allow MTs to generate forces that scale to their length, though detailed mechanisms are still lacking and may vary between systems [24][25][26][27][28][29] . Integration of these forces at the scale of asters that grow to fill the cell volume, yield global forces and torques that center and orient centrosome pairs with respect to aster shape anisotropies 30,31 .…”