The visualization of the simulated nuclear movements controlled by S. We computed simulations nuclei with three cMTs nucleated per nucleus Supplemental Video S7 , as well as another set with six cMTs per nucleus, and quantified the movements see summary in Supplemental Table S2. However, the S. We performed this experiment knowing that A. The simulation indicates that an increase of the cMT growth rate, possibly through the adjusted influence of MT-associated proteins, without changing the catastrophe rate could have been sufficient to induce movements of nuclei against the cytoplasmic stream and also nuclear bypassing.
This scenario, however, would have worked only with a simultaneous fold density increase of cortical Num1 patches, as demonstrated in the next section. The minus end—directed MT motor dynein is responsible for all active nuclear movements in A. It localizes to minus ends and plus ends of cMTs and also along cMTs. Hyphae with inactivated dynactin or Num1 show severely reduced active nuclear movements concomitant with enrichment of dynein at cMT plus ends Grava et al.
These phenotypes and the observed onset of pulling, when a cMT slides along the hyphal cortex, described by the same authors, support a mechanism for cortical pulling known from studies in S. Recently it was demonstrated that dynein is directly switched on by the cortical anchor Num1 Lammers and Markus, Knowing the close evolutionary relation between S.
Because the cortical density of Num1 patches is unknown, we ran simulations with different numbers of randomly distributed cortical anchors. As described earlier, we envisage that these anchors will engage cMTs that are within their reach and immediately recruit dynein. The duration of a pulling event is then determined by the off-rate of the motor domain to the cMT see Materials and Methods.
In terms of nuclear movements, this simplified model is sufficient because forces are created only when dynein is anchored at the cortex and engaged with a cMT. Hence, varying the absolute number of anchors in the simulation can be qualitatively compared with the phenotypes of changing the overall dynein expression level in live cells.
Experimentally reducing the expression level of the dynein heavy chain by truncating the AgDYN1 promoter decreases oscillatory and bypassing-movement frequencies Grava et al.
The reduction in density also increases the movement frequency ratio Figure 5B , top; by favoring forward movements induced by the cytoplasmic flow , decreases the frequency of bypassing events Figure 5B , middle , and increases the frequency of tumbling events Figure 5B , bottom , as previously described in vivo for the promDYN1 and promDYN1 strains, in which the DYN1 promoter was shortened to or base pairs of the original sequence upstream of the start codon, thereby reducing gene expression Grava et al.
Above a certain threshold of anchor density, the pattern of nuclear movements is constant and determined purely by cMT encounters with cortex-bound Num1 patches. The value of the threshold is lower with six cMTs per nucleus Figure 5C , bottom than with three cMTs per nucleus Figure 5C , top , indicating that increasing the density of anchors can compensate for a reduced count of cMTs.
This can be understood in terms of dynein pulling on a single cMT being sufficient to move a nucleus. In the saturated regime in which anchors are in excess, the frequency ratio is close to 1 Figure 5D , left.
In other words, not every cMT contacting the cortex in vivo is pulled by dynein. Taken together, these results show that, despite necessary simplifications, our model has captured how nuclear movements depend on dynein as measured in vivo. The dots stand for individual simulations, and the box indicates the mean and SDs. Results obtained with , , and 20 anchors are plotted in gray, turquoise, and lime green, respectively. C Frequencies of forward lighter and backward darker movements as a function of the number of anchors, with three cMTs gray; top or six cMTs orange; bottom per nucleus.
Each vertical line at 20, , and marks the position of the parameter values used in B. The three vertical lines mark the position of the parameter values used in B.
Of interest, an amount of 20 anchors per hypha segment, which corresponds to 0. The fact that at this density only very few movements are produced in our simulation Figure 5, A and B demonstrates that A. Specifically, our simulations suggest that a fold increase in anchor density would allow enough cMT capture to promote sufficient nuclear movements. To further explore the role of cMT number on the balance between forward and backward movements, we searched for its importance in the context of varying flow speeds.
Indeed, hypha growth speed— and the resulting cytoplasmic flow—was previously shown to affect the balance between forward and backward movements Lang et al. However, the role of cMT number in this balance has not been investigated yet.
We therefore ran simulations with flow speeds randomly varying between 0 and 0. The cMT length was controlled as in wild type. For either condition, with three or six cMTs per nucleus, we generated random values for the flow speed and ran three simulations for each of them.
For both conditions, the frequency of forward movements was roughly independent of flow speed frequencies being lower with six cMTs, on average; Figure 6A , whereas backward movements decreased with increasing flow speed, and this decrease was more pronounced if the nuclei nucleated three cMTs Figure 6B. The movement-frequencies ratio thus remains quite stable for nuclei nucleating six cMTs but gets higher and highly biased toward forward movements with increasing flow speed for nuclei nucleating three cMTs Figure 6C.
Of note, the values of frequencies and ratios observed in our simulations are in agreement with the values measured experimentally, once these are plotted according to the naturally occurring variable hypha growth rates Figure 6, A—C , blue dots. Visualizations of nuclear movement patterns for both conditions at a flow speed of 0 and 0. However, at a flow speed of 0. Is this clear difference between three and six cMTs per nucleus also seen when flow speeds are tested in hyphae with altered average cMT lengths, as in the bik1 or kip3 mutants?
A The frequency of forward movements as a function of increasing cytoplasmic flow from 0 to 0. Simulation values are plotted in gray three cMTs per nucleus and orange six cMTs per nucleus and experimental values in blue. B Plot of the frequency of backward movements as a function of increasing cytoplasmic flow from 0 to 0. Colors as in A. The x -coordinates of the center of individual nuclei 1—5 are plotted in different colors, and the dashed line indicates the applied flow speed.
Top, example of a simulation with three cMTs. Bottom, example of a simulation with six cMTs. E Simulated nuclear positions along time with a flow speed of 0. Same explanation as D. Finally, because hyphal growth can reach speeds as high as 0.
We thus ran additional simulations with flow speeds now randomly varying between 0 and 0. Of interest, the movement-frequencies ratios remained much lower for nuclei nucleating six cMTs than for nuclei nucleating three cMTs even at very high flow speeds Figure 6F. Taken together, these results suggest that having additional cMTs may reduce the bias for forward movements that occurs at rapid hyphal growth, that is, large flow speeds. This also argues for an evolutionary advantage of spending more time in the G2 phase of the nuclear cycle as compared with a S.
The cytoplasm of A. We ran three sets of simulations to test the influence of organelles Figure 7. In the first set, hyphae were lacking simulated organelles Figure 7A.
In the second set, mitochondria occupying 8. A soft excluded-volume interaction is present between all objects see Materials and Methods. The averages for nuclear motility parameters determined from these simulations are summarized in Supplemental Table S4. All of these differences are small, which may indicate that the load on dynein motors is only a small fraction of their stall force, because the viscous drag on the nucleus and the impeding surrounding objects do not provide much resistance.
We next asked whether, as for cMT number, the presence of organelles could also change the balance of movements as a function of hypha growth speed. We thus ran simulations with random flow speeds as described for Figure 6 , with no or high crowding. For the two conditions, the curves representing the frequencies of forward and backward movements and their ratio overlapped for all values of the cytoplasmic flow speed Figure 7C and Supplemental Figure S3B.
Taken together, these computations show that the larger organelles affect nuclear dynamics. Unfortunately, the very likely additional influence of the different forms of the endoplasmic reticulum ER could not be investigated.
ER structures close to the nuclear envelop, within hyphae, and close to the cortex were observed by electron tomography Gibeaux et al. A Snapshots of simulations with uncrowded and highly crowded cytoplasm. Average duration of forward movements top left , average duration of backward movements top right , frequency of bypassing events bottom left , and frequency of tumbling events bottom right. C Plots of the frequencies of forward left and backward middle movements and their ratio right as a function of increasing cytoplasmic flow from 0 to 0.
Colors as in B. Prior genetic and live-imaging studies showed that cMT factors and the dynein motor protein were necessary for the active movements of nuclei in multinucleated hyphae of A.
From these data, it was possible to hypothesize that the oscillatory movements of nuclei in growing hyphae of A. This now seems to be a viable hypothesis. By simulating the process from first principles, we demonstrated here that the pulling action of cortically anchored dynein motors on cMTs originating from the SPB is sufficient to explain active nuclear movements observed in vivo in a quantitative manner.
Of importance, the obtained agreement between experiments and models was not achieved by adjusting various parameters to fit the desired behavior.
Instead, the key parameters of the model, except one, were previously determined experimentally see Table 2 , including the diameter of the cell, the densities and dimensions of the nuclei and other objects Gibeaux et al. These most recent values allowed us to estimate the catastrophe rate by fitting the length distribution.
We used the motile and force parameters of yeast dynein, which had been measured in single-molecule biophysical studies. The only unknown biological parameter was the density of cortical anchors in the simulation, which encompasses unknown factors such as the concentration of dynein molecules in the cell and the effectiveness of the transport, activation, and anchoring mechanisms.
We therefore explored the effect of this parameter systematically Figure 5. As expected, reducing the quantity of anchors in the cell directly reduced or disabled nuclear movements, but increasing anchor density quickly led to a plateau in which every cMT contacting the cortex found at least one force generator Figure 5C.
We selected an intermediate value, which allowed us to fit all of the experimental data see Figure 3 and summary of the quantifications in Table 1. The model reproduced the leading position of the SPB on the nucleus during the movements Supplemental Video S4 and recapitulated the rates of forward and backward movements observed for different values of the cytoplasmic flow both qualitatively and quantitatively Figure 6. By comparing the observed motion of the nuclei and the dependence in the simulation as a function of the density of cortical anchors, we concluded that not every cMT contacting the cortex would be pulled by dynein Figure 5.
This indicates that cytoplasmic flow and dynein-generated forces both contribute significantly to nuclear motions. This is interesting because the associated motions are physically of a different nature.
Cytoplasmic flow is a convective motion, and the total distance traveled is proportional to time,. The dynein-mediated movements, however, are stochastically directed toward or away from the hypha tip, producing without flow and at long time scales a diffusive motion characterized by the relation.
It seems more advantageous biologically to remain away from this regime in order to benefit both from a convective motion that keeps the nuclei equidistant to the growing tip of the hyphae and from the dynein-mediated active diffusion, which permutes nuclei. This means that the cell must avoid excessive cortical pulling on its cMTs by keeping the density of anchors below a certain threshold or via some other mechanism.
The model revealed some interesting findings that help us reinterpret recent experimental results. First, the simulations matched the in vivo observations better with six cMTs nucleated per nucleus than with three Table 1. We interpret this to reflect that a high proportion of nuclei carry duplicated side-by-side SPBs, which is consistent with the fact that, although SPBs nucleate three cMTs on average Gibeaux et al.
Of importance, this model also highlighted several adjustments that A. Specifically, cMTs became 4-fold longer, mostly through an increased growth rate, making them able to reach the cortex Figure 4. In addition, the density of anchors at the cortex also had to increase, possibly fold, as suggested by our simulations, to allow enough cMT capture Figure 5. Of interest, these adaptations seem enough to provide robustness with respect to the high, and changing, organelle density required for hyphal growth Figure 7.
By keeping our model minimal, we could thus demonstrate that a small set of ingredients is enough to explain the basis of the nuclear movements observed in the growing hyphae of A. Nevertheless, some open questions remain. For example, we did not include nuclear division, the true elongation of the hyphae, or their branching geometry.
In addition, the growth of cMTs occurs at a constant speed in our model but could be regulated, for example, by cortical ER, which is substantial in budding yeast West et al.
The model omitted the formation of septa because this only occurs in older regions of the hyphae. These processes will all be exciting to simulate in the future, but additional work is required to extend and exploit the model.
A process of nuclear repulsion was proposed Anderson et al. These territories increase in size as a nucleus approaches mitosis. They might be mediated by cMT, as it was suggested earlier that cMTs from neighboring nuclei could interact with and repulse each other Philippsen et al. However, live-cell imaging and high-resolution analysis of the cMT cytoskeleton by electron tomography did not reveal such interactions Lang et al. The mechanism of the repulsion is thus unknown, precluding its implementation in the simulation.
Nuclei repulsion in A. We thus derived such distributions from the 12 reference live-cell movies and 12 simulations Supplemental Figure S1D. We confirmed that nuclei are not distributed randomly in live hyphae but instead are separated by a characteristic distance.
For the simulations, we found however, a distribution that is close to what would be expected if the nuclei were randomly positioned, with a minor indication for nuclear repulsion Supplemental Figure S1D; see legend for more details.
Nuclear movements were different between three or six cMTs emanating per nucleus but remained similar in many aspects, especially with regard to their bypassing frequencies Table 1.
Still, the reported bypassing frequencies are six times higher for a nucleus in G1 than in G2 Gibeaux et al. According to our model, the duplication state of the SPB, however, is not expected to account for this observation. This thus raises a more general and fascinating question: how can a nucleus control its movements while progressing through the nuclear cycle?
Regulating cMT dynamics at the plus end can lead to direct changes in nuclear behavior Figure 4 and Supplemental Figure S2 , but how could different SPBs contained in a common cytoplasm provide variable cMT dynamics? The challenge is that both the site of force production and the plus end of the cMT that is pulling a nucleus may be distant from this nucleus.
They may be located closer to another nucleus, such that any diffusible substance emitted by a nucleus would not target the productive cMT. Nature has found a solution, however: during mitosis in S. This is the case for Kar9 Liakopoulos et al. Of interest, the asymmetric localization of Kar9 to one SPB and MT plus ends requires a fine regulation through the cyclin-dependent kinase Cdc Bik1 binds directly to Kar9 and promotes its phosphorylation, which affects its asymmetric localization to one SPB and associated cMTs Moore et al.
It is therefore possible to imagine that a nucleus, by adjusting the state of the SPBs, could control plus-end cMT dynamics throughout the nuclear cycle and therefore its movements. However, whether this is the case in the multinucleated hyphae of A. It is relevant to note that dynein is symmetrically distributed to preanaphase SPBs of A. Hence, investigating the nature of mechanisms able to regulate the motile machinery as a function of the nucleus cycle will be an exciting task for future research.
Finally, our study highlights that, beyond its usefulness to validate a particular model, modular software such as Cytosim can be used to simulate the cytoskeleton in many different configurations and thus offers a way to unify our understanding of nuclear migration across the eukaryotic kingdoms.
The methods used to generate these movies are described in the corresponding references. It is yet to be determined whether the polyploid giant cells are returning to the trophozoite stage with respect to cell size and DNA content with time or not. Even without any genomic recombination such cell fusion events agamic cell fusion can be important because through the increased nutrient reserves and resulting polyploidy and hybrid vigor, it can increase cell survival in adverse conditions Comai, ; Goodenough and Heitman, The formation of multinucleated and polyploid cells by cell fusion was also reported in many cancers, and the resulting genome reorganizations facilitated metastasis and drug resistance in cancer Weihua et al.
Similarly, the MGC also possesses the potential to induce phenotypic variations in Entamoeba though this hypothesis is yet to be tested. The three main developmental pathways of amoebozoans: sporulation, encystation and sexual macrocyst pathway were controlled by the environmental conditions O'Day and Keszei, It could be possible that like encystation, MGC pathway is a stress response mechanism and activated by the nutrient and osmotic stress caused by the encystation media.
While encystation helps to survive adverse conditions by forming a resistant cyst, MGC pathway can introduce hybrid fitness and beneficial genomic changes and ensure the survival of Entamoeba in a changing environment. But so far no other stress conditions tested like oxidative or heat shock, induced MGC formation.
The in vitro encystation is conducted using an axenic culture but the intestinal bacteria have been shown to influence characteristics like DNA content and virulence Bracha and Mirelman, ; Mukherjee et al.
For example in the Choanoflagellate Salpingoeca rosetta , sexual reproduction is enhanced by bacteria Vibrio fischeri by inducing cell aggregates in which the cells underwent extensive fusion Woznica et al.
Like cysts, MGC were also formed inside cell aggregates, so the initial cell signaling associated with encystation or the expression of meiotic genes may have caused a few cells to gain fusion competency and start the MGC pathway. Encystation is the ancestral survival mechanism of all amoebozoa Kawabe et al.
Copromyxa protea and Sappinia diploidea form double walled sexual cyst by fusion of two amoebae Walochnik et al. Sexual reproductions and encystations were probably present in the life cycle of last eukaryotic common ancestor LECA. Cell fusion and meiosis during encystation might have helped them to survive as dormant cysts in adverse environmental conditions by providing genetic redundancy and recombinational DNA repair, and that may be associated with the evolution of sex Cavalier-Smith, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Akopyants, N. Demonstration of genetic exchange during cyclical development of Leishmania in the sand fly vector.
Science , — Ali, I. PLoS Negl. Arroyo-Begovich, A. Identification of the structural component in the cyst wall of Entamoeba invadens. CrossRef Full Text. Bakker-Grunwald, T. Entamoeba histolytica as a model for the primitive eukaryotic cell. Today Regul. PubMed Abstract Google Scholar. Bennett, R. Rapid mechanisms for generating genome diversity: whole ploidy shifts, aneuploidy, and loss of heterozygosity.
Cold Spring Harb Perspect Med. Completion of a parasexual cycle in Candida albicans by induced chromosome loss in tetraploid strains. EMBO J. Birky, C. Sex: Is Giardia doing it in the dark? Biron, D. Nature Bracha, R. Virulence of entamoeba histolytica trophozoites. Effects of bacteria, microaerobic conditions, and metronidazole. Brown, M. Slime molds among the Tubulinea Amoebozoa : molecular systematics and taxonomy of Copromyxa.
Protist , — Byers, J. Entamoeba invadens : restriction of ploidy by colonic short chain fatty acids. Parasitol 3 SPEC. Carpenter, M. Nuclear inheritance and genetic exchange without meiosis in the binucleate parasite Giardia intestinalis. Cavalier-Smith, T. Origin of the cell nucleus, mitosis and sex: roles of intracellular coevolution.
Direct Cho, J. Crithidia fasciculata induces encystation of Entamoeba invadens in a galactose-dependent manner. Comai, L. The advantages and disadvantages of being polyploid. Coppi, A. The enteric parasite Entamoeba uses an autocrine catecholamine system during differentiation into the infectious cyst stage. Das, S. De-linking of S phase and cytokinesis in the protozoan parasite Entamoeba histolytica. Ehrenkaufer, G. The genome and transcriptome of the enteric parasite Entamoeba invadens , a model for encystation.
Genome Biol. Ene, I. The cryptic sexual strategies of human fungal pathogens. Forche, A. The parasexual cycle in Candida albicans provides an alternative pathway to meiosis for the formation of recombinant strains.
PLoS Biol. Fraser, J. Same-sex mating and the origin of the Vancouver Island Cryptococcus gattii outbreak. Nature , — Gilchrist, C. A multilocus sequence typing system MLST reveals a high level of diversity and a genetic component to Entamoeba histolytica virulence.
BMC Microbiol. Goodenough, U. Origins of eukaryotic sexual reproduction. Cold Spring Harb Perspect Biol. Grigg, M. Success and Virulence in Toxoplasma as the result of sexual recombination between two distinct ancestries. Cyclin D1-positive cells in the seminiferous tubules were located in the first layer of the wall and the positive cells were part of spermatogonial cells. No positive signals were found in multinucleated cells Fig. A marked immunopositive signal of Bax protein was detected in all seminiferous tubules of day 30 and 33 mouse testis.
Bax-positive cells located between layers 1 and 6 had strong immunoreactive signals and were also found in multinucleated cells. The positive cells may be spermatogonia, primary spermatocytes, secondary spermatocytes, round spermatids and multinucleated cells Fig. Caspase 3 protein immunoreactive signal was detected in a small number of seminiferous tubules in day 30 and 33 mouse testis. Caspase 3-positive cells were scattered in each layer of the seminiferous tubules and a marked immunoreactive signal was detected in multinucleated cells.
Cell morphology revealed that the positive cells were multinucleated cells, spermatogonia, primary spermatocytes, secondary spermatocytes and round spermatids Fig. In day 33 testicular tissue, spermatogonia, primary spermatocytes, secondary spermatocytes and sperm cells exhibited a strong apoptotic signal and were detected in seminiferous tubules. Multinucleated cells did not reveal a positive apoptotic signal Fig. The ratio of the seminiferous tubules containing multinucleated cells in mouse testis indicated that the rates from days 1 to 20 were 0 Table I and Fig.
The appearance of multinucleated cells in mouse testis seminiferous tubules began at day 23 and the rate was maintained at an elevated level between days 23 and It began to decline at day 36 and remained at a lower level in the cell phases that followed Table I and Fig.
Quantification of multinucleated cells in the seminiferous tubules indicated that multinucleated cell numbers peaked at day 33 and were maintained at a relatively stable state in the remaining phases Table I and Fig. Ratio of seminiferous tubules containing multinucleated cells in normal mouse testis development.
Number of multinucleated cells in seminiferous tubules during mouse testis development. The current study evaluated multinucleated cell appearance and potential roles during normal testicular development. Multinucleated cells have been described as being present primarily in pathological processes To the best of our knowledge, the present study has, for the first time, shown that during normal development of the mouse testis, multinucleated cells appeared in sections of the seminiferous tubules at postnatal days 23, 27, 30, 33, 36, 40, 47, 50 and 54, suggesting that multinucleated cells exist in various stages of the normal developmental process in mouse testis.
Given this phenomenon, it is hypothesized that multinucleated cells appear in pathological processes and in normal testicular development. Multinucleated cells were identified between postnatal days 23 and 33 and peaked at day Multinucleated cells were first observed at postnatal day 23 in the center of the seminiferous tube cavity with similar nucleus size as secondary spermatocytes and spermatids.
Our previous study revealed that secondary spermatocytes and a small number of round spermatids may first be observed on postnatal day 23 in the seminiferous tubules of the mouse Therefore, given the time, location and nuclear morphology, these multinucleated cells may be derived from the secondary spermatocytes and spermatids. Following this, the potential role of multinucleated cells during mouse testicular development was investigated. Spermatogenesis is the process by which SSCs self-renew and differentiate into sperm.
The role of multinucleated cells in SSC proliferation and differentiation was analyzed. In the present study, cyclin D1 was expressed in the spermatogonia. Expression of cyclin D1 during active cell cycle is consistent with its role in promoting the transition of the cell cycle from G1 to S phase.
In the current study, PCNA was expressed in spermatogonia and primary spermatocytes, consistent with a previous study by Zhang et al which demonstrated that PCNA plays a role in spermatogonia and primary spermatocytes of the DNA replication process Immunostaining revealed no positive immune signals in multinucleated cells, indicating that cyclin D1 and PCNA was not expressed in these cells.
The observations indicated no physiological and biochemical activities of the G1 or S-phase appearing within the cells with no DNA replication occurring.
Cell , 47—60 Crasta, K. DNA breaks and chromosome pulverization from errors in mitosis. Nature , 53—58 Zhang, C. Chromothripsis from DNA damage in micronuclei.
Nature , — Ly, P. Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. Cell Biol. Soto, M. Cell Rep. Brito, D. Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Zhu, Y. Post-slippage multinucleation renders cytotoxic variation in anti-mitotic drugs that target the microtubules or mitotic spindle.
Cell Cycle 13 , — Pedersen, R. Profiling DNA damage response following mitotic perturbations. Mirzayans, R. Cancers 10 , — Draviam, V. Chromosome segregation and genomic stability. Mythily, D. Pleiotropic effects of human papillomavirus type 16 E6 oncogene expression in human epithelial cell lines.
Gasco, M. The p53 pathway in breast cancer. Breast Cancer Res. Overton, K. Basal p21 controls population heterogeneity in cycling and quiescent cell cycle states. Natl Acad. Arora, M. Endogenous replication stress in mother cells leads to quiescence of daughter cells. Spencer, S. The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit.
Cell , — Cappell, S. Irreversible APC Cdh1 inactivation underlies the point of no return for cell-cycle entry. Gookin, S. A map of protein dynamics during cell-cycle progression and cell-cycle exit. PLoS Biol. Dai, L. Kwon, J. Controlling depth of cellular quiescence by an Rb-E2F network switch. Moser, J. Control of the Restriction Point by Rb and p Shi, J. Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic.
Cancer 24 , T83—T96 Chromosomes trapped in micronuclei are liable to segregation errors. Cell Sci. Shrestha, R. Kuhn, J. Spindle assembly checkpoint satisfaction occurs via end-on but not lateral attachments under tension. Wood, K. Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.
Weihua, Z. Formation of solid tumors by a single multinucleated cancer cell. Cancer , — Muller, P. Fujiwara, T. Cytokinesis failure generating tetraploids promotes tumorigenesis in pnull cells. Thompson, S. Proliferation of aneuploid human cells is limited by a pdependent mechanism. Santaguida, S. Chromosome mis-segregation generates cell-cycle-arrested cells with complex karyotypes that are eliminated by the immune system.
Cell 41 , — Liu, S. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Cell 49 , — Zimmermann, M. Science , — Chapman, J. Corrigan, A.
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