Cell migration and division in amoeboid-like fission yeast.
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ABSTRACT:
SUBMITTER: Flor-Parra I
PROVIDER: S-EPMC3892166 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A key question in cytokinesis is how the cell division plane is positioned. Whereas microtubules of the mitotic apparatus specify the division site in animal cells, we show here that the nucleus plays this role in the fission yeast Schizosaccharomyces pombe. By centrifuging cells to move the nucleus, we find that the nucleus (or a nuclear-associated structure) actively influences the position of contractile ring assembly during early mitosis. Displacement of the nucleus during this induction period can lead to formation of multiple rings. The nucleus signals its position in a microtubule-independent manner by emitting the protein mid1p. Furthermore, movement of ring fragments together minimizes formation of multiple division sites. These dynamic mechanisms of ring positioning provide a robust coordination of nuclear and cell division.
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Project description:Animal and fungal cells divide through the assembly, anchoring, and constriction of a contractile actomyosin ring (CAR) during cytokinesis. The timing and position of the CAR must be tightly controlled to prevent defects in cell division, but many of the underlying signaling events remain unknown. The conserved heterotrimeric protein phosphatase PP2A controls the timing of events in mitosis, and upstream pathways including Greatwall-Ensa regulate PP2A activity. A role for PP2A in CAR regulation has been less clear, although loss of PP2A in yeast causes defects in cytokinesis. Here, we report that Sds23, an inhibitor of PP2A family protein phosphatases, promotes the symmetric division of fission yeast cells through spatial control of cytokinesis. We found that sds23? cells divide asymmetrically due to misplaced CAR assembly, followed by sliding of the CAR away from its assembly site. These mutant cells exhibit delayed recruitment of putative CAR anchoring proteins including the glucan synthase Bgs1. Our observations likely reflect a broader role for regulation of PP2A in cell polarity and cytokinesis because sds23? phenotypes were exacerbated when combined with mutations in the fission yeast Ensa homologue, Igo1. These results identify the PP2A regulatory network as a critical component in the signaling pathways coordinating cytokinesis.
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Project description:Association with microtubules inhibits the fission of mitochondria in Schizosaccharomyces pombe. Here, we show that this attachment of mitochondria to microtubules is an important cell-intrinsic factor in determining cell division symmetry. By comparing mutant cells that exhibited enhanced attachment and no attachment of mitochondria to microtubules (Dnm1Δ and Mmb1Δ, respectively), we show that microtubules in these mutants displayed aberrant dynamics compared to wild-type cells, which resulted in errors in nuclear positioning. This translated to cell division asymmetry in a significant proportion of both Dnm1Δ and Mmb1Δ cells. Asymmetric division in Dnm1Δ and Mmb1Δ cells resulted in unequal distribution of mitochondria, with the daughter cell that received more mitochondria growing faster than the other daughter cell. Taken together, we show the existence of homeostatic feedback controls between mitochondria and microtubules in fission yeast, which directly influence mitochondrial partitioning and, thereby, cell growth. This article has an associated First Person interview with the first author of the paper.
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Project description:Eukaryotic cells assemble actomyosin rings during cytokinesis to function as force-generating machines to drive membrane invagination and to counteract the intracellular pressure and the cell surface tension. How the extracellular matrix affects actomyosin ring contraction has not been fully explored. While studying the Schizosaccharomyces pombe 1,3-β-glucan-synthase mutant cps1-191, which is defective in division septum synthesis and arrests with a stable actomyosin ring, we found that weakening of the extracellular glycan matrix caused the generated spheroplasts to divide under the nonpermissive condition. This nonmedial slow division was dependent on a functional actomyosin ring and vesicular trafficking, but independent of normal septum synthesis. Interestingly, the high intracellular turgor pressure appears to play a minimal role in inhibiting ring contraction in the absence of cell wall remodeling in cps1-191 mutants, as decreasing the turgor pressure alone did not enable spheroplast division. We propose that during cytokinesis, the extracellular glycan matrix restricts actomyosin ring contraction and membrane ingression, and remodeling of the extracellular components through division septum synthesis relieves the inhibition and facilitates actomyosin ring contraction.
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Project description:Amoeboid cell migration is characterized by frequent changes of the direction of motion and resembles a persistent random walk on long time scales. Although it is well known that cell migration is typically driven by the actin cytoskeleton, the cause of this migratory behavior remains poorly understood. We analyze the spontaneous dynamics of actin assembly due to nucleation promoting factors, where actin filaments lead to an inactivation of these factors. We show that this system exhibits excitable dynamics and can spontaneously generate waves, which we analyze in detail. By using a phase-field approach, we show that these waves can generate cellular random walks. We explore how the characteristics of these persistent random walks depend on the parameters governing the actin-nucleator dynamics. In particular, we find that the effective diffusion constant and the persistence time depend strongly on the speed of filament assembly and the rate of nucleator inactivation. Our findings point to a deterministic origin of the random walk behavior and suggest that cells could adapt their migration pattern by modifying the pool of available actin.
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Project description:Mitochondria are essential and dynamic eukaryotic organelles that must be inherited during cell division. In yeast, mitochondria are inherited asymmetrically based on quality, which is thought to be vital for maintaining a rejuvenated cell population; however, the mechanisms underlying mitochondrial remodeling and segregation during this process are not understood. We used high spatiotemporal imaging to quantify the key aspects of mitochondrial dynamics, including motility, fission, and fusion characteristics, upon aggregation of misfolded proteins in the mitochondrial matrix. Using these measured parameters, we developed an agent-based stochastic model of dynamics of mitochondrial inheritance. Our model predicts that biased mitochondrial fission near the protein aggregates facilitates the clustering of protein aggregates in the mitochondrial matrix, and this process underlies asymmetric mitochondria inheritance. These predictions are supported by live-cell imaging experiments where mitochondrial fission was perturbed. Our findings therefore uncover an unexpected role of mitochondrial dynamics in asymmetric mitochondrial inheritance.
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Project description:The invasion of nerves by cancer cells, or perineural invasion (PNI), is potentiated by the nerve microenvironment and is associated with adverse clinical outcomes. However, the cancer cell characteristics that enable PNI are poorly defined. Here, we generated cell lines enriched for a rapid neuroinvasive phenotype by serially passaging pancreatic cancer cells in a murine sciatic nerve model of PNI. Cancer cells isolated from the leading edge of nerve invasion showed a progressively increasing nerve invasion velocity with higher passage number. Transcriptome analysis revealed an upregulation of proteins involving the plasma membrane, cell leading edge, and cell movement in the leading neuroinvasive cells. Leading cells progressively became round and blebbed, lost focal adhesions and filipodia, and transitioned from a mesenchymal to amoeboid phenotype. Leading cells acquired an increased ability to migrate through microchannel constrictions and associated more with dorsal root ganglia than nonleading cells. ROCK inhibition reverted leading cells from an amoeboid to mesenchymal phenotype, reduced migration through microchannel constrictions, reduced neurite association, and reduced PNI in a murine sciatic nerve model. Cancer cells with rapid PNI exhibit an amoeboid phenotype, highlighting the plasticity of cancer migration mode in enabling rapid nerve invasion.
| S-EPMC10151474 | biostudies-literature
Project description:In animal cells, the mitotic spindle is aligned perpendicular to the axis of cell division. This ensures that sister chromatids are separated to opposite sides of the cytokinetic actomyosin ring (CAR). We show that, in fission yeast, spindle rotation is dependent on the interaction of astral microtubules with the cortical actin cytoskeleton. Interaction initially occurs with a region surrounding the nucleus, which we term the astral microtubule interaction zone (AMIZ). Simultaneous contact of astral microtubules from both poles with the AMIZ directs spindle rotation and this requires both actin and two type V myosins, Myo51 and Myo52. Astral microtubules from one pole only then contact the CAR, which is located at the centre of the AMIZ. We demonstrate that the anillin homologue Mid1, which dictates correct placement of the CAR, is necessary to stabilise the mitotic spindle perpendicular to the axis of cell division. Finally, we show that the position of the mitotic spindle is monitored by a checkpoint that regulates the timing of sister chromatid separation.
| S-EPMC381420 | biostudies-literature
Project description:For polarized growth of cells, protein kinases regulate the assembly of cytoskeletal structures at the correct time and place. Large cytoskeletal structures must also be assembled in a regulated manner during cytokinesis and cell separation. We performed a visual screen to identify cell polarity protein kinases that might also function in cytokinesis and cell separation. We found that the Cdc42-activated protein kinase Pak1 (also called Orb2 and Shk1) colocalizes with the assembling cytokinetic ring and remains in the cell middle during septation. Mutations in pak1 led to defects in cytokinetic ring assembly and cell separation, as well as previously known cell polarity defects. We performed a phosphoproteomic screen and identified novel Pak1 targets that were verified as direct substrates in vitro. Top targets included proteins that function in polarized growth, cytokinesis, and septation. For cytokinesis, we found that Pak1 regulates the localization of its substrates Mid1 and Cdc15 to the cell cortex and the cytokinetic ring. For cell separation, Pak1 phosphorylates the RNA-binding protein Sts5 to prevent its assembly into P-body granules. The cell separation defect of pak1 mutants was suppressed by a non-phosphorylatable sts5 mutant. These results show that Pak1 acts directly on components of the cytokinetic ring, but unexpectedly promotes the later stages of cell division by inhibiting the assembly of ribonucleoprotein granules. More broadly, our work reveals that cell polarity signaling proteins coordinate diverse events to promote cell division at the end of the cell cycle.
2019-07-02 | MSV000084047 | MassIVE
Project description:Mitosis in eukaryotic cells employs spindle microtubules to drive accurate chromosome segregation at cell division. Cells lacking spindle microtubules arrest in mitosis due to a spindle checkpoint that delays mitotic progression until all chromosomes have achieved stable bipolar attachment to spindle microtubules. In fission yeast, mitosis occurs within an intact nuclear membrane with the mitotic spindle elongating between the spindle pole bodies. We show here that in fission yeast interference with mitotic spindle formation delays mitosis only briefly and cells proceed to an unusual nuclear division process we term nuclear fission, during which cells perform some chromosome segregation and efficiently enter S-phase of the next cell cycle. Nuclear fission is blocked if spindle pole body maturation or sister chromatid separation cannot take place or if actin polymerization is inhibited. We suggest that this process exhibits vestiges of a primitive nuclear division process independent of spindle microtubules, possibly reflecting an evolutionary intermediate state between bacterial and Archeal chromosome segregation where the nucleoid divides without a spindle and a microtubule spindle-based eukaryotic mitosis.
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