Cdc42 GTPase Activating Proteins (GAPs) Maintain Generational Inheritance of Cell Polarity and Cell Shape in Fission Yeast

Abstract

The highly conserved small GTPase Cdc42 regulates polarized cell growth and morphogenesis from yeast to humans. We previously reported that Cdc42 activation exhibits oscillatory dynamics in Schizosaccharomyces pombe cells. Mathematical modeling suggests that this dynamic behavior enables a variety of symmetric and asymmetric Cdc42 distributions to coexist in cell populations. For individual wild type cells, however, growth follows a stereotypical pattern where Cdc42 distribution is initially asymmetrical in young daughter cells and becomes more symmetrical as cell volume increases, enabling bipolar growth activation. To explore whether different states of Cdc42 activation are possible in a biological context, we examined S. pombe rga4∆ mutant cells, lacking the Cdc42 GTPase activating protein (GAP) Rga4. We found that monopolar rga4∆ mother cells divide asymmetrically leading to the emergence of both symmetric and asymmetric Cdc42 distributions in rga4∆ daughter cells. Using genetic screening approaches to identify mutants that alter the rga4∆ phenotype, we tested the predictions of different computational models that reproduce the unequal fate of daughter cells. We found experimentally that the unequal distribution of active Cdc42 GTPase in daughter cells is consistent with an unequal inheritance of another Cdc42 GAP, Rga6, in the two daughter cells. Our findings highlight the crucial role of Cdc42 GAP protein localization in determining the morphological fate of cell progeny and ensuring consistent Cdc42 activation and growth patterns across generations.

Fission Yeast Polarization: Modeling Cdc42 Oscillations, Symmetry Breaking, and Zones of Activation and Inhibition

“…Meanwhile rga6∆ cells have been found to be slightly more monopolar, with smaller relative Cdc42 fluctuations compared to wild-type [39]. This comparison to experiments suggests that there is more to polarity regulation of these mutant cells than simply changing a single rate constant of our model (see recent results in [54]).…”

Cdc42 reactivation at growth sites is regulated by local cell-cycle-dependent loss of its GAP Rga4

“…A recent report has shown that presence of the GAPs at the cortex prevents local Cdc42 activation even upon localization of the scaffold Scd2, which recruits Scd1 to the cortex (Lamas et al, 2020b). Another preprint suggests that Cdc42 GAP levels in daughter cells determine the pattern of polarized growth in those cells (Pino et al, 2020). These reports and our findings together indicate that loss of Rga4 from the cell ends after mitosis is necessary to allow Cdc42 activation at these ends, so long as the MOR pathway is active.…”

The Multiple Functions of Rho GTPases in Fission Yeasts

“…In higher eukaryotes, it is unknown whether Rho GAPs also regulate the cortical localization and function of septins. Another function of Rga6 in polarized growth might be to link the growth history of the mother cell to Cdc42 activation in daughter cells [160].…”