Asymmetric cell division generates cell diversity across all kingdoms of life. For example, stem cells form daughters that differentiate and the ones that replenish the stem cell pool. Defects in polarity and asymmetric cell division lead to developmental problems and disease. We use the budding yeast S. cerevisiae as a model system to understand the mechanisms and functions of asymmetric cell division.
A notable trait of budding yeast cell division is ageing. Indeed, yeast mother cells have a limited division potential. Damages such as protein aggregates accumulate in the mother cell. How they are asymmetrically inherited to allow rejuvenation of daughter cells is still poorly understood. Beyond identifying the mechanisms of asymmetric cell division, we follow the idea that a merit to ageing may be the cellular ability to keep memories of their past adaptations to cope better with future stress.
We discovered a new type of epigenetic memory that is based on the aggregation of the mRNA binding protein Whi3. In response to mating pheromone, haploid yeast cells arrest in G1 and grow in the shape of a “shmoo” towards their partner. Cells exposed to pheromone only can escape the pheromone arrest, re-enter the cell cycle and produce daughter cells (see figure 1). Mother cells maintain this pheromone refractory state for the remainder of their life span. In contrast, daughter cells are born naïve and respond to pheromone. The pheromone refractory state depends on the inactivation of Whi3. Whi3 inhibits translation of mRNA encoding Cln3, the G1 cyclin required for the G1 to S phase transition. Whi3 contains prion-like domains (PrD) that promote an inactivating conformational change upon pheromone treatment. We termed this type of protein mnemon. A mnemon is a protein that change of fold and super-assembly can encode a cellular memory. It is specifically induced by a stimulus and inherited asymmetrically during cell division. In contrast, prions are usually stochastically induced and symmetrically inherited during cell division. PrD containing proteins are very common in most living organisms and many of these molecules cause proteopathies such as neurodegenerative diseases or Creutzfeldt-Jakob disease. We test the idea that many of them behave as mnemons and we aim at understanding their biology in physiological and pathological contexts.