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Regulation of fission yeast cytokinesis by membrane lipids and septins

Abstract : Cell division is an essential process required for the proliferation of unicellular organisms, for the development of multicellular organisms, as well as for cell renewal within tissues and organs. Defective control of cell division can either lead to cell death, or to cell hyper-proliferation and contribute to cancer progression. Cell division is therefore under the control of very tight regulatory mechanisms. In animals and fungi, its final step, cytokinesis, requires an acto-myosin-based contractile ring that constricts to promote sister cell cleavage. Modifications in the lipid composition of the plasma membrane take place during cell division, with functional impact on cytokinesis.Fission yeast is a simple single cell eukaryotic organism which has been extensively used to study cell division because of its stereotyped rode shape, easy genetics and short generation time. In particular, this model system has proved very powerful for the molecular dissection of contractile ring assembly. However remarkably little is known on how membrane lipids regulate contractile ring assembly. In the first part of my PhD, my objective was to study how lipids could regulate contractile ring positioning in fission yeast. I have combined fission yeast genetics with live-cell imaging of contractile ring assembly from precursor nodes to understand how ergosterol levels affect division plane positioning. I have found that increased ergosterol levels prevent F-actin assembly from cytokinetic precursor nodes by the formin Cdc12, avoiding their compaction into a medially placed contractile ring. Since the stability of F-actin cables was not altered altogether and the phenotype could be partially rescued by inhibition of the Arp2/3 complex which competes with formins, we propose that increasing ergosterol levels in the plasma membrane may inhibit the activity of the formin Cdc12.In addition to the contractile ring, cytokinesis involves an additional component of the cytoskeleton, the septins, which form filaments at the division site. Septins are a family of conserved GTP binding proteins whose deletion leads to cytokinetic defects. They also serve as scaffolds for protein-protein interactions and/or as diffusion barriers for protein compartmentalization in cytokinesis and beyond. In fission yeast, in contrast to budding yeast, septins are late at the division site and are only involved in late stages of cytokinesis, to promote sister cell separation. In the second part of my PhD, I decided to explore the dynamic behavior of septins and decipher how they are regulated. Using live cell imaging and precise cell cycle timers, I have identified a new step in the recruitment of septin to the cell cortex in the proximity of the contractile acto-myosin ring, in a broad meshwork that then compacts into a tight ring. I have also found evidence that the anillin-like protein Mid2 is necessary to promote this compaction and may act as a bundler for septin filaments. However, analysis of mutants blocked in mitosis shows that this protein is not sufficient to accomplish this task. Moreover, I have determined that high Cdk activity allows septins and Mid2 initial recruitment and assembly, but the SIN pathway also plays a role in promoting their recruitment at the cell middle and is then required to drive their compactio. Additionally, I have found that PIP2 levels influence not only the amount of septins and Mid2 filaments associated at the medial cortex together with their compaction but also the timing of septin recruitment to the division site. This demonstrates that septin assembly relies on complex regulations coordinated by the cell cycle machinery.
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Federica Arbizzani. Regulation of fission yeast cytokinesis by membrane lipids and septins. Cellular Biology. Université Paris sciences et lettres, 2019. English. ⟨NNT : 2019PSLET027⟩. ⟨tel-02887503⟩

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