Integration of Multiple Metabolic Signals Determines Cell Fate Prior to Commitment

Abstract

Cell-fate decisions are central to the survival and development of both uni- and multicellular organisms. It remains unclear when and to what degree cells can decide on future fates prior to commitment. This uncertainty stems from experimental and theoretical limitations in measuring and integrating multiple signals at the single-cell level during a decision process. Here, we combine six-color live-cell imaging with the Bayesian method of statistical evidence to study the meiosis/quiescence decision in budding yeast. Integration of multiple upstream metabolic signals predicts individual cell fates with high probability well before commitment. Cells "decide" their fates before birth, well before the activation of pathways characteristic of downstream cell fates. This decision, which remains stable through several cell cycles, occurs when multiple metabolic parameters simultaneously cross cell-fate-specific thresholds. Taken together, our results show that cells can decide their future fates long before commitment mechanisms are activated.

Functional interrelationships between carbohydrate and lipid storage, and mitochondrial activity during sporulation in Saccharomyces cerevisiae

“…Cells were grown in YPG medium for doubling time calculation (Arguello‐Miranda et al, ). Cells grown in early exponential phase (OD 600 < 0.3) were diluted to OD 600 ≈ 0.05.…”

“…In budding yeast, larger cells tend to sporulate more efficiently (Day et al, ). Cell size, which we have shown to be highly predictive but not causative of entry into meiosis, is a general readout for these multiple metabolic parameters (Arguello‐Miranda et al, ). A major regulator of cell size is Cln3, a conserved G 1 cyclin that promotes G 1 ‐ to S‐phase transition.…”

“…In addition to trehalose and glycogen metabolism, our previous study also identified mitochondrial biomass as an excellent predictor for meiosis (Arguello‐Miranda et al, ). These results were consistent with the essential requirement of functional mitochondria for meiosis (Zhao et al, ).…”

“…This crucial last step is of paramount importance for sexual reproduction because defects in gametogenesis are frequent causes of infertility and can be lethal for many organisms (Liu et al, ; Marchal, Vigneron, Perreau, Bali‐Papp, & Mermillod, ; Nebreda & Ferby, ; Neiman, ). Despite its importance, the regulation of gametogenesis by the metabolic status of the cell is far less understood in comparison with the mechanisms that control the preceding meiotic processes, such as recombination or meiotic nuclear divisions (Arguello‐Miranda, Liu, Wood, Kositangool, & Doncic, ; Hochwagen, ; Kassir et al, ; Sarkar, Millar, & Arumugam, ; Weidberg, Moretto, Spedale, Amon, & van Werven, ).…”

“…A major regulator of cell size is Cln3, a conserved G 1 cyclin that promotes G 1 ‐ to S‐phase transition. Hence, the G 1 period is extended in cln3Δ mutants, which are larger and sporulate more efficiently (Arguello‐Miranda et al, ; Cross, ; Nash, Tokiwa, Anand, Erickson, & Futcher, ; Wijnen, Landman, & Futcher, ). Several cellular components, such as mitochondria, vacuoles, total protein, and RNA content, scale with cell size (Schmoller & Skotheim, ), but it is not known whether an increase in these factors can compensate for reduced sporulation efficiency in carbohydrate‐deficient backgrounds.…”