Replicative age negatively influences proliferative capacity since early stages in a Whi5-dependent manner

Abstract

Clonal populations exhibit phenotypic variation despite being composed of genetically identical cells under the same environmental conditions. Proliferation rate also shows this heterogeneity, but the underlying mechanisms remain poorly understood. In this study, we combined single-cell microencapsulation with confocal microscopy to develop a new experimental approach for analyzing budding yeast cell lineages and determining the age of every cell within each microcolony. We found that most slow-growing lineages are founded by young mother cells that have undergone only a few cell divisions, typically between 1 and 4. This reduction in proliferative capacity is linked to the expression levels of the cell cycle regulator Whi5, which increase with the number of replication cycles, even since the earliest stages. We also found that the increased levels of Whi5 are due to the higher accumulation of its mRNA during the S/G2/M phases of young mother cells compared to newborn cells. Our results show that the proliferative structure of a cell population is progressively shaped in each mitotic cycle, starting from the very first division, when a mother cell has the opportunity to establish a slow proliferating lineage. Possible mechanisms of Whi5 action to mediate this effect are discussed.