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Ultimate proximate divisions: towards an integrated understanding of evolutionary and mechanistic aspects of mitosis

A new mechanistic model of spindle structure and dynamics explains its diversity across 100 million years of evolution.

The eminent evolutionary biologist, Ernst Mayr, famously distinguished between two types of causation in biology: proximate and ultimate. Proximate causes are the mechanistic explanations for how biological systems do what they do. Ultimate causes are the evolutionary explanations for why biological systems are what they are. This is an important epistemological distinction and, as a practical matter, most biologists focus on investigating only one of these two types of causes. However, there is an increasing appreciation among many researchers that integrating evolutionary and mechanistic approaches can lead to deep insights. This can be addressed at any level of biological organisation, from molecules to organisms, including at the scale of the cell, the fundamental building block of life.

Figure: The spindle in a nematode, segregating chromosomes (red).

When a cell divides, its DNA, which is packed into compact structures called chromosomes, gets divided into the two daughter cells. The ultimate cause of chromosome segregation is to provide each daughter cell a complete copy of the genetic material. The proximate cause of chromosome segregation is the spindle, a stunningly beautiful subcellular structure that elongates and pushes the chromosomes apart (see figure). But what about other aspects of the spindle: what determines its size; its shape; how fast and how much it elongates? Any of these questions can be addressed from a mechanistic perspective or an evolutionary perspective. 

In 2015, the Needleman lab (Harvard University), in collaboration with Charlie Baer (University of Florida), Erik Andersen (Northwestern University), Thomas Müller-Reichert (University of Technology, Dresden) and Marie Delattre (Ecole Normale Superieure, Lyon), published an evolutionary study of the morphology and dynamics of the spindle in nematodes. They investigated variations in the spindle between different individuals of the same species, and variations in spindles between different species. They found that natural selection doesn’t directly impact the morphology and dynamics of the spindle at all. Surprisingly, selection acts predominantly on the size of cells, and only indirectly influences the spindle through its scaling with cell size. This provides an ultimate explanation for spindle morphology and dynamics in nematodes. But it leaves open the question: what causes the spindle to scale with cell size?

Now, the Needleman lab has published the results of a new study with Mike Shelley (Flatiron Institute), Thomas Müller-Reichert and Mat Rockman (New York University) that provides an answer. They used the natural genetic variations between individuals within species to test models of spindle scaling, and they dissected the forces acting on the spindle by cutting it with a laser. The results of these experiments led them to construct a mathematical model that makes quantitatively accurate predictions of how the constituents of the spindle, and the forces acting between them, produce the spindle’s size, elongation and scaling with cell size.  This provides a proximate explanation for spindle morphology and dynamics in nematodes.

While understanding evolutionary and mechanistic aspects of the spindle are both fascinating, the most remarkable results emerge when these two perspectives are integrated. The evolutionary work shows that cell size is the object of selection; the mechanistic model predicts how varying cell size leads to variations in spindle morphology and dynamics. Combining these two findings explains the diversity in spindles across 100 million years of nematode evolution. 

Still, there is much more work to do. These studies did not address many important topics, from a detailed molecular understanding of genetic changes, to fascinating aspects of spindle motion and force production. And there is far more than 100 million years of evolution of the spindle to consider, and far more organisms than just nematodes. Whatever future studies reveal, unifying evolutionary and mechanistic approaches will certainly be a productive path forward.

Reference

Stoichiometric interactions explain spindle dynamics and scaling across 100 million years of nematode evolution.
Farhadifar R, Yu CH, Fabig G, Wu HY, Stein DB, Rockman M, Müller-Reichert T, Shelley MJ, Needleman DJ. Elife. 2020 Sep 23;9:e55877. doi: 10.7554/eLife.55877. PMID: 32966209; PMCID: PMC7511230.

Other references

Scaling, Selection, and Evolutionary Dynamics of the Mitotic Spindle.
Farhadifar R, Baer CF, Valfort AC, Andersen EC, Müller-Reichert T, Delattre M, Needleman DJ. x Curr Biol. 2015 Mar 16;25(6):732-740. doi: 10.1016/j.cub.2014.12.060. Epub 2015 Feb 12. PMID: 25683802.

Link to article in Current Biology
PubMed link

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Reference

Stoichiometric interactions explain spindle dynamics and scaling across 100 million years of nematode evolution.
Farhadifar R, Yu CH, Fabig G, Wu HY, Stein DB, Rockman M, Müller-Reichert T, Shelley MJ, Needleman DJ. Elife. 2020 Sep 23;9:e55877. doi: 10.7554/eLife.55877. PMID: 32966209; PMCID: PMC7511230.