The assembly of a bipolar microtubule-based spindle is crucial for the accurate and timely segregation of the chromosomes into the two daughter cells during mitosis.
Three microtubule nucleation pathways function in mitotic cells to contribute microtubules to the assembling spindle, namely the centrosome-, chromatin- and microtubule-mediated pathways.
Microtubules nucleated from the centrosomes find the chromosomes via 'search and capture' — a process that relies on the dynamic instability of microtubules — which allows them to search space to contact the chromosomes. When a microtubule contacts a kinetochore, it is captured and becomes stabilized to form kinetochore fibres (K-fibres).
The speed and efficiency of chromosome capture is promoted by the chromatin-mediated pathway that biases microtubule nucleation and stabilization to the vicinity of the chromosomes.
Microtubules are also generated from within the spindle itself via Augmin, which promotes microtubule nucleation from pre-existing microtubules. This nucleation increases the density of microtubules within the spindle and thus contributes to its robustness.
Although the nucleation pathways are at least partially redundant, they are integrated to provide an intricate balance of microtubule nucleation that ensures the fidelity of chromosome segregation and the timely completion of mitosis. In the absence of any one of the pathways, spindle assembly still occurs — although with increased use of the remaining pathways — but mitosis takes longer and this can result in genome instability.
The mitotic spindle has a crucial role in ensuring the accurate segregation of chromosomes into the two daughter cells during cell division, which is paramount for maintaining genome integrity. It is a self-organized and dynamic macromolecular structure that is constructed from microtubules, microtubule-associated proteins and motor proteins. Thirty years of research have led to the identification of centrosome-, chromatin- and microtubule-mediated microtubule nucleation pathways that each contribute to mitotic spindle assembly. Far from being redundant pathways, data are now emerging regarding how they function together to ensure the timely completion of mitosis. We are also beginning to comprehend the multiple mechanisms by which cells regulate spindle scaling. Together, this research has increased our understanding of how cells coordinate hundreds of proteins to assemble the dynamic, precise and robust structure that is the mitotic spindle.
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The authors thank S. Royle and A. McAinsh for critical reading of the manuscript. They apologize to authors whose work they could not cite owing to space constraints. The work in the L.P. laboratory is funded by the Canadian Institute for Health Research (MOP 123468, MOP 130507, MOP 142492), the Natural Sciences and Engineering Research Council of Canada (RGPIN 355644–13), the Krembil Foundation, the Canadian Cancer Society and Genome Canada. L.P. holds a Canada Research Chair in Centrosome Biogenesis and Function. S.L.P. holds a European Union Horizon 2020 Marie Skłodowska-Curie Global Fellowship (No. 702601).
The authors declare no competing financial interests.
- Microtubule minus end
Microtubules are composed of 13 protofilaments formed by head-to-tail arrays of α- and β-tubulin dimers, which means that microtubules are polar structures with two distinct ends. The minus end is the slow-growing end of microtubules.
- Microtubule plus end
The fast-growing end of microtubules.
- Guanine nucleotide exchange factor
(GEF). A protein that activates GTPases by stimulating the release of GDP to allow the binding of GTP.
Microtubule plus end-directed motor proteins that bind to chromosome arms and contribute to metaphase chromosome alignment.
- Abnormal spindle-like microcephaly-associated protein
(ASPM). The human orthologue of Drosophila melanogaster Asp, it contributes to mitotic spindle assembly; defective forms are associated with autosomal recessive primary microcephaly (MCPH).
- Spindle equator
The widest part of the mitotic spindle. It is the area in the centre of the spindle where microtubules from the opposite poles overlap and the chromosomes align.
- Microtubule catastrophe
The transition from microtubule growth to shrinkage that results in rapid microtubule disassembly.
- Nuclear lamina
A dense fibrillar network of intermediate filaments, lamins and associated proteins, which lines the inner surface of the nuclear membrane.
- Cell rounding
The shape change that most animal cells undergo as they enter mitosis. It is seen as a shift from a spread, elongated shape into a compact, spherical morphology.
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Prosser, S., Pelletier, L. Mitotic spindle assembly in animal cells: a fine balancing act. Nat Rev Mol Cell Biol 18, 187–201 (2017). https://doi.org/10.1038/nrm.2016.162
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