Mitotic spindle assembly in animal cells: a fine balancing act

Prosser, Suzanna L.; Pelletier, Laurence

doi:10.1038/nrm.2016.162

Cited by 346 publications

(336 citation statements)

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“…Complex control and surveillance mechanisms have evolved to ensure the fidelity and robustness of mitotic and meiotic processes. As the chromatin is highly compacted during cell division, these mechanisms rely in large part on post-translational modifications (PTMs) of proteins involved in the assembly and orientation of the mitotic spindle (Prosser and Pelletier, 2017), the attachment and segregation of chromosomes (Musacchio, 2015;Musacchio and Desai, 2017), and the formation and ingression of a cleavage furrow that separates the two daughter cells (Fig. 1) (D'Avino et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Citron kinase – renaissance of a neglected mitotic kinase

D’Avino

2017

Journal of Cell Science

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Cell division controls the faithful segregation of genomic and cytoplasmic materials between the two nascent daughter cells. Members of the Aurora, Polo and cyclin-dependent (Cdk) kinase families are known to regulate multiple events throughout cell division, whereas another kinase, citron kinase (CIT-K), for a long time has been considered to function solely during cytokinesis, the last phase of cell division. CIT-K was originally proposed to regulate the ingression of the cleavage furrow that forms at the equatorial cortex of the dividing cell after chromosome segregation. However, studies in the last decade have clarified that this kinase is, instead, required for the organization of the midbody in late cytokinesis, and also revealed novel functions of CIT-K earlier in mitosis and in DNA damage control. Moreover, CIT-K mutations have recently been linked to the development of human microcephaly, and CIT-K has been identified as a potential target in cancer therapy. In this Commentary, I describe and re-evaluate the functions and regulation of CIT-K during cell division and its involvement in human disease. Finally, I offer my perspectives on the open questions and future challenges that are necessary to address, in order to fully understand this important and yet unjustly neglected mitotic kinase.

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Section: Introductionmentioning

confidence: 99%

Citron kinase – renaissance of a neglected mitotic kinase

D’Avino

2017

Journal of Cell Science

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“…RANGAP1 decreases the local RANGTP concentration at KTs. In physiological mitosis, RANGTP activates KT-directed nucleation of MTs (Tulu et al, 2006) that contribute to the spindle organisation (reviewed by Cavazza and Vernos, 2015;Prosser and Pelletier, 2017). KT-associated RANGAP1 is critical to RANGTP turnover at KTs, and hence to modulation of KT-directed MT nucleation and K-fibre stability (Torosantucci et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Importin-β and CRM1 control a RANBP2 spatiotemporal switch essential for mitotic kinetochore function

Gilistro

Turris

Damizia

et al. 2017

Journal of Cell Science

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Protein conjugation with small ubiquitin-related modifier (SUMO) is a post-translational modification that modulates protein interactions and localisation. RANBP2 is a large nucleoporin endowed with SUMO E3 ligase and SUMO-stabilising activity, and is implicated in some cancer types. RANBP2 is part of a larger complex, consisting of SUMO-modified RANGAP1, the GTP-hydrolysis activating factor for the GTPase RAN. During mitosis, the RANBP2-SUMO-RANGAP1 complex localises to the mitotic spindle and to kinetochores after microtubule attachment. Here, we address the mechanisms that regulate this localisation and how they affect kinetochore functions. Using proximity ligation assays, we find that nuclear transport receptors importin-β and CRM1 play essential roles in localising the RANBP2-SUMO-RANGAP1 complex away from, or at kinetochores, respectively. Using newly generated inducible cell lines, we show that overexpression of nuclear transport receptors affects the timing of RANBP2 localisation in opposite ways. Concomitantly, kinetochore functions are also affected, including the accumulation of SUMOconjugated topoisomerase-IIα and stability of kinetochore fibres. These results delineate a novel mechanism through which nuclear transport receptors govern the functional state of kinetochores by regulating the timely deposition of RANBP2.

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“…Although autocatalytic growth can be regulated by limiting the catalyst, such mechanisms are unlikely to function in the large cells of developing eggs such as Xenopus, where resources are not limiting (17). Understanding the role of microtubule nucleation in setting the size of spindles is limited by the fact that little is known about the rate, distribution, and regulation of microtubule nucleation in spindles (12,13). This is partly because of the lack of methods to measure microtubule nucleation in spindles.…”

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

“…http://dx.doi.org/10.1101/174078 doi: bioRxiv preprint first posted online Aug. 9, 2017; factors other than pre-existing microtubules (e.g. diffusible cues in the cytoplasm) stimulate nucleation (12)(13)(14)(15)(22)(23)(24).If microtubule nucleation depends on pre-existing microtubules, altering microtubule stability should change the nucleation profile-a microtubule that exists for a longer time would have a higher probability to stimulate the creation of more microtubules.To test this scenario, we increased microtubule stability by inhibiting the depolymerizing kinesin MCAK (25) using antibodies. MCAK inhibition led to a dramatic increase in monopole size (see Fig.…”

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confidence: 99%

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Autocatalytic microtubule nucleation determines the size and mass of spindles

Decker¹,

Oriola²,

Dalton³

et al. 2017

Preprint

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Regulation of size and growth is a fundamental problem in biology. A prominent example is the formation of the mitotic spindle, where protein concentration gradients around chromosomes are thought to regulate spindle growth by controlling microtubule nucleation (1,2). Previous evidence suggests that microtubules nucleate throughout the spindle structure (3-5). However, the mechanisms underlying microtubule nucleation and its spatial regulation are still unclear. Here, we developed an assay based on laser ablation to directly probe microtubule nucleation events in Xenopus laevis egg extracts. Combining this method with theory and quantitative microscopy, we show that the size of a spindle is controlled by autocatalytic growth of microtubules, driven by microtubule-stimulated microtubule nucleation. The autocatalytic activity of this nucleation system is spatially regulated by the limiting amounts of active microtubule nucleators, which decrease with distance from the chromosomes. Thus, the size of spindles is determined by the distance where one microtubule nucleates on average less than one new microtubule. This mechanism . CC-BY-NC 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/174078 doi: bioRxiv preprint first posted online Aug. 9, 2017; provides an upper limit to spindle size even when resources are not limiting and may have implications for spindle scaling during development (6,7). Main textA general class of problems in biology is related to the emergence of size and shape in cells and tissues. Reaction diffusion mechanisms have been broadly successful in explaining spatial patterns in developmental biology as well as some instances of intracellular structures (8,9). The mitotic spindle, a macromolecular machine responsible for segregating chromosomes during cell division, is thought to be a classic example of such reaction diffusion processes. A diffusible gradient of the small GTPase Ran emanating from chromosomes has been shown to trigger a cascade of events that result in the nucleation of microtubules, the main building blocks of the spindle (1, 2). The spatial distribution of microtubule nucleation is key for understanding size and architecture of large spindles. This is because microtubules in these spindles are short and turnover rapidly (3,10,11). The mechanisms underlying the spatial regulation of microtubule nucleation, however, are still unclear (12, 13).One possibility is that the interplay between Ran-mediated nucleation and microtubule turnover governs spindle assembly (1, 2). However, the role of the Ran gradient in determining spindle size is still controversial. For instance, in cell culture systems, the length scale of the Ran gradient does not correlate with spindle size (5).A second possibility is that autocatalytic growth accounts for spindle assembly via microtubule-stimulated microtubule nucleation (4,(14)(15)(16). However, autocatalytic . CC-BY-N...

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Mitotic spindle assembly in animal cells: a fine balancing act

Cited by 346 publications

References 179 publications

Citron kinase – renaissance of a neglected mitotic kinase

Citron kinase – renaissance of a neglected mitotic kinase

Importin-β and CRM1 control a RANBP2 spatiotemporal switch essential for mitotic kinetochore function

Autocatalytic microtubule nucleation determines the size and mass of spindles

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