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The spindle assembly checkpoint functions during early development in non-chordate embryos

Janet Chenevert, Marianne Roca, Lydia Besnardeau, Antonella Ruggiero, Dalileh Nabi, Alex McDougall, Richard R. Copley, Elisabeth Christians, Stefania Castagnetti

Posted on: 3 April 2019

Preprint posted on 19 March 2019

Article now published in Cells at http://dx.doi.org/10.3390/cells9051087

To SAC or not to SAC? Shedding light on an evolutionary conundrum in early embryonic divisions

Selected by Maiko Kitaoka

Background

Most eukaryotic cells use the spindle assembly checkpoint (SAC) to ensure faithful chromosome segregation in each round of cell division by delaying mitotic progression until all chromosomes are properly attached to spindle microtubules at their kinetochores. However, early embryonic divisions notably lack a checkpoint response despite the importance to maintain genome fidelity, ploidy, and stability to establish a new developing organism.

For example, the early embryonic cleavages of both Xenopus frogs and zebrafish do not have cell cycle checkpoints until the mid-blastula transition and zygotic genome activation. Embryos continue to cycle through these early divisions despite the presence of microtubule depolymerizing drugs, suggesting that the SAC is silenced or weakened in these fast division cycles. Studies in C. elegans have also suggested that the larger cell size at earlier embryonic divisions causes the SAC signaling cascade to be too dilute to mount a meaningful response. As cells decrease in size, a sufficient kinetochore-to-cell volume ratio threshold is reached, allowing for stronger signaling responses. However, in other large-celled organisms such as sea urchins and clams, treatment with microtubule depolymerizing drugs caused a delay in mitotic progression, suggesting that these embryos may be SAC competent.

Given the variability of SAC signaling between organisms and cell size, the authors used a multi-species comparative analysis to determine if the SAC activity and response correlated with any particular cellular characteristic or evolutionary group. They examined ~15 different organisms across multiple metazoan groups and combined their findings with those from the literature of previously characterized organisms, such as Xenopus, Danio rerio, Drosophila, and C. elegans. Interestingly, they find no correlation between SAC activity and cell size, chromosome number, or kinetochore-to-cell volume ratio. Instead, they stumbled upon the novel discovery that SAC silencing arose during the evolution of chordates.

Key findings

In order to determine which species activated SAC signaling for cell division, the authors treated two-celled embryos with nocodazole to completely depolymerize microtubules. They monitored the mitotic marker phospho-histone H3 (pH3) over time to assess whether each species arrests in mitosis or continues to cycle through cell division, thus demonstrating whether embryos respond to or lack SAC signaling, respectively. Similar to the published data in Xenopus and zebrafish, the chordate tunicate P. mammillata showed pH3 oscillations and continued to cycle, while multiple species of sea urchin (echinoderms), the mussel M. galloprovincialis (a mollusk), and the jellyfish C. hemisphaerica (a cnidarian) delayed mitotic progression. The authors confirmed these mitotic delays were due to SAC activation by inhibiting the SAC kinase Mps1, which usually recruits other checkpoint proteins at unattached kinetochores. Treatment with the Mps1 inhibitor reversine shortened the nocodazole-induced mitotic arrest and restored cell cycle timing, which confirms the SAC dependence of the mitotic arrest.

Experimental schematic (A) and two examples of different responses to nocodazole treatment, where the tunicate P. mammillata continues to cycle through cell divisions (B) and the sea star H. attenuata arrests in mitosis (C). From Figure 1.

 

Since cell size has been shown to affect the strength of the SAC, the authors compared the cell size, kinetochore number, and kinetochore-to-cell volume ratio in 2-celled embryos of their species and additionally analyzed previous published data from the model organisms, C. elegans, D. melanogaster, and X. laevis. Interestingly, none of these parameters correlated with the difference in SAC responses.

Through their multi-species analysis, strikingly only the chordates (the tunicate P. mammillata, X. laevis, and D. rerio) did not trigger a mitotic delay in early embryogenesis. The authors also analyzed another tunicate species, C. intestinalis, and a cephalochordate lancelet, B. lanceolatum, to examine whether the lack of SAC response is a chordate-specific feature. Both additional species continue to cycle through the early cleavages, similar to fish and frog embryos, suggesting that SAC silencing during the early embryonic divisions evolved through the chordate lineage.

Evolutionary lineage of the species tested in this analysis, where chordates are the only ones that silence SAC signaling. From Figure 4.

 

This study poses an interesting evolutionary conundrum – What is the selective advantage associated with loss of SAC signaling in chordate embryos? Given the importance of reproductive success and the integral role of faithful chromosome segregation, it’s unclear why loss of the SAC would be favored. The work here opens the door for other comparative analyses and investigations in different species into the molecular mechanisms of the SAC in these early cleavages.

Questions for the authors

How much have SAC components evolved through the different evolutionary groups examined in this analysis? Do cnidarians have fewer SAC components than chordates, for example?

Since chordates lack SAC signaling in the early embryo, are they less prone to chromosome mis-segregation in these divisions or are chordates more robust and able to tolerate small amounts of chromosome mis-segregation better than other evolutionary groups of metazoans?

Why would chordates evolve to silence the SAC, i.e., what is the advantage to the loss of SAC signaling? Previous studies argued that the speed of divisions was necessary for externally developing organisms to reach a more motile stage (tadpoles, larvae, etc) to avoid predators, but since there doesn’t seem to be an incompatibility between the fast divisions and SAC activation, the advantage is less clear.

Tags: early development, embryonic cleavages, evolution, mitosis, mitotic checkpoint, sac, spindle assembly checkpoint

doi: https://doi.org/10.1242/prelights.9655

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