Size-Dependent Expression of the Mitotic Activator Cdc25 Suggests a Mechanism of Size Control in Fission Yeast

Abstract

Summary Proper cell size is essential for cellular function. Nonetheless, despite more than 100 years of work on the subject, the mechanisms that maintain cell size homeostasis are largely mysterious [1]. Cells in growing populations maintain cell size within a narrow range by coordinating growth and division. Bacterial and eukaryotic cells both demonstrate homeostatic size control, which maintains population-level variation in cell size within a certain range, and returns the population average to that range if it is perturbed [1, 2]. Recent work has proposed two different strategies for size control: budding yeast has been proposed to use an inhibitor-dilution strategy to regulate size at the G1/S transition [3], while bacteria appear to use an adder strategy, in which a fixed amount of growth each generation causes cell size to converge on a stable average [4-6]. Here we present evidence that cell size in the fission yeast Schizosaccharomyces pombe is regulated by a third strategy: the size dependent expression of the mitotic activator Cdc25. The cdc25 transcript levels are regulated such that smaller cells express less Cdc25 and larger cells express more Cdc25, creating an increasing concentration of Cdc25 as cell grow and providing a mechanism for cell to trigger cell division when they reach a threshold concentration of Cdc25. Since regulation of mitotic entry by Cdc25 is well conserved, this mechanism may provide a wide spread solution to the problem of size control in eukaryotes.

Cell Size Control via an Unstable Accumulating Activator and the Phenomenon of Excess Mitotic Delay

“…As cells grow, Cdc25 levels will increase until they reach the size threshold required to dephosphorylate Cdk1, at which point they will enter mitosis. Consistent with this model, my lab and others have shown that, in fission yeast, Cdc25 accumulates in a size‐dependent manner in G2 . The conservation of Cdc25 across fungi and metazoa allows the possibility that Cdc25 accumulation could be a conserved mechanism of cell‐size control.…”

“…Thus, accumulating activator models often propose unstable accumulating activators . Accumulating activators have been proposed to regulate entry into mitosis in a variety of unicellular eukaryotes, including Tetrahymena , Amoeba , and fission yeast …”

“…These graphs are a simple depiction of these concepts. For a formal mathematical treatment of the subject see Figure 4E of Keifenheim et al.…”

“…In fission yeast, the size‐dependent accumulation of Cdc25 appears to be transcriptional . Size‐dependent expression of a transcriptional activator would explain such behavior, but would beg the question of how the transcription factor was expressed in a size dependent manner.…”

“…The fact that specific proteins, such as Whi5 in budding yeast, CDKG1 in Chlamydomonas , and Cdc25 in fission yeast, are being identified for their size‐dependent expression, augurs well for rapid progress in understanding the mechanisms of cell size control in eukaryotes. A major advance in the field would be to show direct requirement for size‐dependent expression of a putative sizer protein in cell size control.…”