MISTIQ

Cells perpetually face the decision to proliferate or to enter a non-dividing state. Quiescence, operationally defined as a temporary proliferation arrest, is the most widespread cellular state on earth. Quiescence establishment, maintenance and exit, by balancing cell proliferation, are key steps involved not only in normal development and tissues homeostasis, but also in major human pathologies such as cancers. Besides quiescent cells have to face the damaging effect of age while preserving their ability to proliferate, the loss of this capacity being at the origin of many age-related diseases. Quiescence is thus at the cross road of major biological processes and is becoming an important emergent research field due to the foreseen impacts on human health. At the cellular level, quiescence establishment is accompanied by the reorganization of many cellular edifices, including organelles, such as mitochondria or the nucleus, and machineries, like the proteasome or the actin cytoskeleton. Most of these rearrangements, primarily uncovered in yeasts, have now been described in plants and/or metazoan models. Yet, the physiological function(s) of these quiescence-specific cellular reorganizations remains enigmatic. One of these intriguing quiescence-specific remodelling concerns microtubules. Indeed, upon quiescence entry in yeast, all the dynamic microtubules found in proliferating cells vanish and a unique bundle composed of extremely stable microtubules is assembled from the centrosome. The molecular mechanisms orchestrating the formation of this stable microtubule bundle is puzzling. Importantly, in yeast, the formation of a stable microtubule bundle is tightly associated with cell survival in quiescence, but the cellular function of this structure remains unknown. Intriguingly, a stable microtubule bundle has been observed in quiescent S. cerevisiae and S. pombe, two genetically distant unicellular eukaryotes suggesting that microtubule stabilization in quiescence could be conserved among eukaryotes. The main objective of the MISTIQ project is to shed light on the properties and the cellular function(s) of the stable microtubule structure specifically assembled in quiescent cells. More precisely, we aim at understanding (i) the molecular mechanisms controlling microtubule bundle nucleation by the centrosome, (ii) the molecular basis of microtubule stabilization in quiescence, and, finally and most importantly, (iii) the cellular function(s) of this essential microtubule structure. To achieve these goals, the Sagot team has joined forces with the Arnal team. Our two laboratories share an expertise in the microtubule field with complementary technical skills covering genetic, biochemistry, cell biology, advanced microscopy (including super resolution, single cell tracking, cryo-electron microscopy and tomography) and cell-free reconstitution of microtubule dynamic properties. We will primary focus on S. cerevisiae, the sole eukaryote for which, to date, quiescence establishment and exit can be controlled, manipulated and followed at the individual cell level for several days. Our long-term goal is to lay the foundations for future studies in mammalian models. That is why, strong of the experience of the Arnal team in studying microtubule stabilization in neurones, we will start exploring the relationships between microtubule stabilization and quiescence maintenance in neural stem cells (NSC). In adult brain, most NSCs are quiescent and their capacity to resume proliferation is critical for regeneration of neurons. Hence, the MISTIQ project should advance the frontiers of the fundamental knowledge on the biology of microtubules in quiescent yeast and should pioneer future exciting research in mammals.