Rôle du cortex polaire dans la mécanique de la cytocinèse dans différents types cellulaires et conséquences de sa perturbation sur le destin cellulaire et l’organisation tissulaire

Cytokinesis is the final step of cell division, ensuring faithful partitioning of cellular material between daughter cells. In metazoans, it relies on the assembly and constriction of an actomyosin contractile ring (CR) that drives plasma membrane ingression between segregating chromatids. Activation of the small GTPase Rho1 by its conserved RhoGEF, Pbl-A, is essential for CR assembly and constriction. The pathway specifying the equatorial zone of Rho1 activity is well established: Pbl-A accumulates at the cell equator through its interaction with the centralspindlin complex. While equatorial contractility has long been recognized as the main driver of furrow ingression, less is known about the contribution of the polar cortex contractility for robust cytokinesis.Using Drosophila neuroblasts as a model, I and other team members uncovered the role of a novel Pbl isoform, Pbl-B, during cytokinesis in parallel to the canonical Pbl-A. While Pbl-A was enriched at the equator, Pbl-B was localized at the plasma membrane and relocated prematurely in the nucleus at the end of cytokinesis. Alternative expression of Pbl-A and B revealed that Pbl-A functioned to focus Rho1 activity at the ring to sustain efficient constriction, while Pbl-B increased contractility at the poles, which was critical to adjust furrow position, thereby preserving correct daughter cell size asymmetry. Our work highlighted how the use of isoforms with distinct localisation makes an essential process more robust. These findings provided the groundwork for my first main thesis project, which focused on understanding how cytokinesis adapts to diverse cell types with specific intrinsic and extrinsic constraints. We reasoned that the two Pbl isoforms with different spatio-temporal patterns of Rho1 activity may provide flexibility to a process that is challenged by diverse tissue features. To address this question, we used the alternative expression of Pbl-A and -B isoforms to manipulate Rho1 activity at the equator and poles in two different cell types: the large, and non-adherent spermatocytes undergoing incomplete cytokinesis, and the adherent and polarized epithelial cells of the notum. Quantitative live imaging revealed that the loss of either isoforms produces similar changes in myosin dynamics in both cell types but with different outcome. In spermatocytes, Pbl-B but not –A was essential for spermatocyte cytokinesis by promoting timely myosin recruitment and efficient CR assembly. Conversely, Pbl-A but no –B was required for robust epithelial cell cytokinesis, by providing the necessary equatorial contractile force to disengage adherens junctions from neighbor cells, a critical step in epithelial cell division. Our comparative study illustrates how cytokinesis adapts to tissue specificity via the modulation of polar and equatorial contractility through the use of Pbl isoforms with distinct spatial activities.The high rate of cytokinesis failure in ∆pbl-A epithelia generated multinucleated cells, providing a unique opportunity to explore the impact of polyploidy on tissue organization. Detailed examination of ∆pbl-A notum architecture identified large multinucleated cells as well as a population of small cells en route to delamination. Long-term imaging showed that many daughter cells delaminated, despite initially completing cytokinesis. Delamination was neither due to spindle orientation defects, nor apoptosis signaling, the two known triggers of epithelial cell extrusion. Instead, it was correlated with an increase in polar cortex contractility associated with blebbing during the preceding cytokinesis. Importantly, delaminated cells were not eliminated and persisted within the basal layer of the tissue, posing the threat that they complete their mesenchymal transition by acquiring oncogenic mutations. Our work identifies a novel mechanism of epithelial-to-mesenchymal transition stemming from mild changes in myosin dynamics during the preceding cytokinesis.