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Aurora B controls microtubule stability to regulate abscission dynamics in stem cells

Snježana Kodba, Amber Öztop, Eri van Berkum, Malina K. Iwanski, Wilco Nijenhuis, Lukas C. Kapitein, Agathe Chaigne

Posted on: 19 March 2024

Preprint posted on 6 March 2024

Aurora B actively drives abscission in pluripotent mouse Embryonic Stem Cells via the stabilisation of microtubule bridges

Selected by Ines Jmel-Boyer

Background

Abscission is the process that physically separates two newly formed cells (1). It can be a lengthy process that needs to be coordinated with DNA replication and DNA segregation (2-4). In order to achieve this, different complexes are recruited in a tightly controlled and timely manner. The process starts at anaphase with the formation of the central spindle, a structure composed of antiparallel microtubule that coordinates the position of the cleavage furrow, and the contraction of the actin ring. This is coordinated by the timely recruitment of the Chromosomal Passenger Complex (Aurora B, INCENP, Survivin, and Borealin) and Plk1. The microtubules remain until the end of abscission and form a bridge with the midbody. The midbody is a structure that serves as a recruitment platform for the ESCRT complex which oversees the physical separation of the cells. It was recently shown that a complex coordination between actin and microtubules is needed for abscission as the microtubule bridge needs to be severed (5) but, up to this point, microtubules were thought to passively contribute to the timing of abscission.

Abscission time and cell fate are linked as mammalian pluripotent stem cells maintain bridges between two dividing cells for several hours, while stem cells exiting the pluripotent state undergo abscission faster (6). In this study, the authors looked at mouse Embryonic Stem Cells (ESC) while these cells transitioned from a “naïve” to an “exiting” state of pluripotency during which abscission takes 6 hours and 2-3 hours, respectively.

Key findings

In this preprint, the authors focus on how abscission duration can be modulated to follow the change in cell fate (during development).

First, they confirmed that bridge maturation takes a few hours in naïve ESC and that abscission occurs faster in exiting ESC compared to naïve ESC.

They showed that Aurora B levels decrease over time, and so does its activity (in both naïve ESC and exiting ESC). Furthermore, Aurora B levels and activity are lower in exiting ESC compared to naïve ESC. Then, the authors demonstrated that decreasing Aurora B activity sped up abscission and led to a faster exit from pluripotency.

Next, the authors looked at the levels of total tubulin and unstable tubulin (tyrosinated) and found that they decreased over time, while acetylated tubulin (stable) transiently increased in naïve ESCs (this also happened to a lesser extent in exiting ESCs). They observed that when Aurora B activity was decreased, the bridges were shorter with less tubulin and concluded that the decrease in Aurora B activity decreases the amount of tubulin and the microtubules stability.

The authors played with the stability of microtubules (using taxol to stabilise microtubules and nocodazole to destabilise them) and looked at the consequences this had on the duration of abscission. They found that upon microtubule destabilisation the number of bridges was lower, a sign of faster abscission, and that the opposite was true for microtubule stabilisation. So overall, they could conclude that stable microtubules prevent abscission.

They then showed that abscission happens asymmetrically on one of the two arms of the bridge (on one side of the midbody). At the end of bridge maturation, the arms showed different levels of stable (acetylated) tubulin and phosphorylated Aurora B. They concluded that, at the end of abscission, Aurora B activity decreases on one of the arms, locally destabilising microtubules and allowing abscission to happen. It was already shown in previous work that the cells retaining the midbody will exit pluripotency slower than the cells that do not inherit it (6).

Finally, the authors wondered what could explain the difference in Aurora B’s presence and activity between naïve ESCs and exiting ESCs. They found that decreasing Wnt signalling increased Aurora B and phosphorylated Aurora B, in turn, reducing the number of bridges (in fixed samples), meaning that abscission occurred faster, and the remaining bridges were shorter.

In summary, the authors showed that Wnt signalling in naïve ESCs resulted in increased Aurora B activity at the bridge, causing a transient increase in microtubule stability, thus delaying abscission. In exiting ESCs, the activity of Aurora B was decreased and as a result, abscission could occur faster.

 

Why I liked this preprint

This preprint shows that microtubule bridges are not passive remnants of the spindle. In fact, they are a driver of abscission dynamics with an impact on cell fate. Furthermore, the authors link a crucial developmental signalling pathway (Wnt) to a very specific mechanism that is conserved in various organisms. Finally, a lot of the findings described in this preprint can be linked to the literature, and the authors could link some of the proteins involved to well-known cytokinetic proteins – such as spastin – that could be regulated by the stability of microtubules, further enhancing our understanding of cytokinesis.

 

References

  1. Andrade V, Echard A. Mechanics and regulation of cytokinetic abscission. Front Cell Dev Biol. 2022;10:1046617.
  1. Amaral N, Vendrell A, Funaya C, Idrissi FZ, Maier M, Kumar A, et al. The Aurora-B-dependent NoCut checkpoint prevents damage of anaphase bridges after DNA replication stress. Nat Cell Biol. 2016;18(5):516-26.
  2. Mendoza M, Norden C, Durrer K, Rauter H, Uhlmann F, Barral Y. A mechanism for chromosome segregation sensing by the NoCut checkpoint. Nat Cell Biol. 2009;11(4):477-83.
  3. Petsalaki E, Zachos G. The Abscission Checkpoint: A Guardian of Chromosomal Stability. Cells. 2021;10(12).
  4. Advedissian T, Frémont S, Echard A. Cytokinetic abscission requires actin-dependent microtubule severing. Nat Commun. 2024;15(1):1949.
  5. Chaigne A, Labouesse C, White IJ, Agnew M, Hannezo E, Chalut KJ, et al. Abscission Couples Cell Division to Embryonic Stem Cell Fate. Dev Cell. 2020;55(2):195-208.e5.

 

doi: https://doi.org/10.1242/prelights.36861

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Author's response

Agathe Chaigne shared

Questions for the authors

-What is the point of having cytoplasmic bridges in stem cells? Does it allow exchanges between cells as it does in the germline (in C. elegans or Drosophila melanogaster)?

That is a very good question and a question we want to study in our lab. In the germline, long lived cytoplasmic bridges are important for transport between cells. In mouse embryonic stem cells, we know that cells can exchange material through the bridges (Chaigne 2020), but it is not known if it has a role in development. We hypothesize that the (at least partial) continuity between the cytoplasm allows cells to remain in a state of pluripotency by allowing homogeneity (and preventing one cell to bifurcate, for example to exit pluripotency too fast or too slow), but we need more evidence!

-Have cytoplasmic bridges been found in stem cells in other organisms than mammals?

Slow abscission happens in several embryos (we reviewed it extensively in Chaigne&Brunet 2022); for example, it was shown in the mouse embryo in Zenker 2017, but also in zebrafish, anemone, and squid embryos. In stem cells, it has been described in cnidarian and ctenophores.

-In Figure 2B, how could you explain the absence of a difference between the naïve ESC and exiting ESC? With the ZM treatment, how could you explain that the Sox1 expression goes down in naïve ESC?

In figure 2B, we normalise the data to the control (so control naïve is at 1 and we compare it to naïve ZM, and control exiting is at 1 and we compare it to exit ZM). There is a difference in control versus exit (all the pluripotency genes are down and Sox1, which is a neural marker, is up), but we are not plotting it because that is not what we wanted to look at. We wanted to show that ZM treatment leads to a global downregulation of pluripotency genes, and upregulation of Sox1. For Sox1, it only does so in the exiting context- I don’t think it’s so surprising because Sox1 is very lowly expressed in naïve cells, with or without ZM.

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