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Microtubule-independent movement of the fission yeast nucleus

Sanju Ashraf, David A. Kelly, Kenneth E. Sawin

Preprint posted on August 30, 2020 https://www.biorxiv.org/content/10.1101/2020.08.29.273409v1.full

Can the nucleus of a cell move in the absence of dynamic microtubules? Ashraf et al. uncover microtubule-independent nuclear movement in fission yeast cells.  

Selected by Leeba Ann Chacko

Categories: cell biology, microbiology

Background: 

 

Figure 1: Taken directly from Fig. 7 of Ashraf et al. 2020 under a CC-BY 4.0 international license depicting models for microtubule independent nuclear movement.

 

The fission yeast is a rod-shaped unicellular eukaryote that divides symmetrically to produce two similar-sized daughter cells. The cells initially grow in a unidirectional manner through polarized tip extension until a length of about 9.0-9.5 microns, then they begin to grow in a bi-directional manner until a length of ~14 μm after which they divide [1].  

During monopolar cell growth, the nucleus is dynamically positioned at the geometric center of the cell through the polymerization-based pushing forces of anti-parallel microtubule bundles that emanate from the microtubule organizing center (MTOC) to the poles of the cell [2-5]. The position of the nucleus dictates the localization of the anillin-like protein, Mid1p, which recruits a series of proteins that aid the assembly of the actomyosin ring for cell division [6]. Tubulin mutants show nuclear-positioning defects, thus affecting the site of cell division and inheritance of cellular components post-mitosis [4]. 

While the importance of microtubule dynamics in positioning the nucleus has been established, it is not known if the nucleus can move in the absence of microtubules. Ashraf et al. show that nuclear movement persists in a unidirectional manner in the absence of microtubules and this movement depends on actin cables that originate from the growing tip of the cell as well as the organization of the endoplasmic reticulum (ER). 

Key findings: 

Monopolar–growing cells require the action of active forces to enable the movement of the nucleus in the direction of the growing cell tip to maintain the position of the nucleus at the gyrometric center of the cell. These forces were thought to depend on the microtubule bundle pushing forces. However, Ashraf et al. showed that even after depolymerizing microtubules using a drug, the nucleus moved at velocities like control cells in the direction of the growing tip thus staying mostly at the geometric center of the cell. The authors refer to this movement as “Microtubule-independent nuclear movement (MINM)”.  

To understand the mechanism behind MINM, the authors looked at actin cables because they extend from the growing tip of the cell towards the inside of the cell and can encounter the nucleus. The authors found that in cells devoid of the actin-nucleator formin 3 (for3), or cells with a single point mutation in the actin-binding region of the Formin Homology 2 domain, the nucleus remained stationary upon depolymerizing microtubules indicating that actin cables are necessary for MINM to occur. 

To check if the physical link between the actin cables and the nucleus is responsible for MINM, the authors compared nuclear movement close to and away from the growing tip by depolymerizing the microtubules and then centrifuging the cells. The nuclei that were displaced away from the growing tip upon centrifugation showed no movement while those that were displaced towards the growing tip continued to move towards it indicating that MINM can occur only if the nucleus is close to actin cables at the growing tip. 

Since class V myosins are involved in actin filament organization, the authors set out to see if these myosins contribute to MINM. While myo51Δ and myoVΔ nuclei showed movement towards the growing tip upon microtubule depolymerization, myo52Δ nuclear movement was more complex wherein a proportion of the cells displayed either no nuclear movement and/or sudden movements which includes movement away from the growing tip. The authors attribute this aberrant nuclear movement observed in microtubule-depolymerized myo52Δ cells to the ability of myo52 to affect actin cable organization.   

As the nuclear envelope and cortex in S. pombe cells are enveloped by the ER, the authors hypothesized that the actin cables may be causing MINM through the ER. To test this, the authors observed nuclear movement in cells devoid of the ER-localized transmembrane proteins, which shows large scale detachment of the ER from the plasma membrane. Interestingly, they found that most of these cells showed no nuclear movement upon microtubule depolymerization indicating that these ER proteins work along with actin cables to enable MINM. 

Lastly, to test whether MINM occurs in the presence of microtubules, the authors looked at nuclear movement in cells devoid of for3 as well as cells devoid of the ER-localized transmembrane proteins. Interestingly, the nucleus in cells without for3 showed increased fluctuations compared to wild-type cells indicating that the presence of actin cables helps dampen the MT-based pushing forces. However, deleting ER-localized transmembrane proteins did not show the same effect and the authors speculate that this is possibly due to the collapse of the ER into the cytoplasm dampens the MT-pushing movement.  

What I liked about this preprint: 

The preprint was very well written and easy to follow. This is the first time I am coming across literature that shows the role of actin cables in moving the nucleus in fission yeast. As soon as I saw the title of this preprint, I was interested! Even though MINM is slow, it influences how the cell divides and that is remarkable to me.  

Questions for the authors: 

  1. Figure 1I shows that in the absence of microtubules, there is no relationship between nuclear velocity and the position of the nucleus. However, Figure 4 shows that in the absence of microtubules, the nuclear velocity is greatest when the nucleus is displaced towards the growing tip and least when it was displaced away from the growing tip. Why do you suppose there is no correlation between the position of the nucleus and nuclear velocity in the first experiment but there is a correlation in the second experiment?
  2. Previous studies have shown that when microtubules are depolymerized in cells under specific conditions, over time the cell begins to display polarity defects [7]. Additionally, cells with shorter microtubules also show polarity defects [4]. Would it be worthwhile to see in which direction the nucleus moves when there are multiple growing tips in a cell? 
  3. It is surprising that despite changes in actin cable organization in both myo52Δ and myoVΔ cells, only myo52Δ nuclei show complex movement. Could there be something more at play besides subtle differences in the actin organization between myo52Δ and myoVΔ cells? 
  4. You have shown that increased nuclear fluctuations in for3Δ mutants could be causing the observed increased frequency of misplaced septa. However, the nuclear fluctuations are unaltered in scsΔ cells and yet there is an increased frequency of misplaced septa in these mutants. If the nuclear dynamics are unaffected in the scsΔ mutants, how are a significant proportion of these cells dividing asymmetrically?  
  5. You have shown that the microtubule bundle numbers are unchanged in for3Δ mutants. However, could changes in microtubule orientation [8] or changes in microtubule dynamics (growth rates, shrinkage rates, catastrophe frequencies and dwell times) contribute to the increased nuclear fluctuations?  

References: 

  1. Hercyk, B.S., et al., A novel interplay between GEFs orchestrates Cdc42 activity during cell polarity and cytokinesis in fission yeast. J Cell Sci, 2019. 132(23).
  2. Hagan, I. and M. Yanagida, Evidence for cell cycle-specific, spindle pole body-mediated, nuclear positioning in the fission yeast Schizosaccharomyces pombe. J Cell Sci, 1997. 110 ( Pt 16): p. 1851-66.
  3. Tran, P.T., et al., A mechanism for nuclear positioning in fission yeast based on microtubule pushing. J Cell Biol, 2001. 153(2): p. 397-411.
  4. Sawin, K.E. and H.A. Snaith, Role of microtubules and tea1p in establishment and maintenance of fission yeast cell polarity. J Cell Sci, 2004. 117(Pt 5): p. 689-700.
  5. Daga, R.R., A. Yonetani, and F. Chang, Asymmetric microtubule pushing forces in nuclear centering. Curr Biol, 2006. 16(15): p. 1544-50.
  6. Paoletti, A. and F. Chang, Analysis of mid1p, a protein required for placement of the cell division site, reveals a link between the nucleus and the cell surface in fission yeast. Mol Biol Cell, 2000. 11(8): p. 2757-73.
  7. Sawin, K.E. and P. Nurse, Regulation of cell polarity by microtubules in fission yeast. J Cell Biol, 1998. 142(2): p. 457-71.
  8. Feierbach, B. and F. Chang, Roles of the fission yeast formin for3p in cell polarity, actin cable formation and symmetric cell division. Curr Biol, 2001. 11(21): p. 1656-65.

Tags: actin, cytoskeleton, formin, microtubules, nucleus, s.pombe

Posted on: 6th October 2020

doi: https://doi.org/10.1242/prelights.25059

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