Abstract
Author SummaryHow long should a cell wait to respond to an environmental change? While many pathways such as those affecting chemotaxis respond to environmental signals quickly, in other contexts a cell may want to defer its response until long after the signal's onset—sometimes waiting multiple cell cycles. How can cells create “timers” to regulate these long deferrals? We study this question in the bacterium Bacillus subtilis, which responds to stress by transforming into a dormant spore. We show that B. subtilis can defer sporulation for extended time periods by first undergoing multiple rounds of growth and proliferation, and only then sporulating. The timer for this deferral is a pulsed positive feedback loop, which ratchets up the concentration of the sporulation master-regulator Spo0A to a critical level over multiple cell cycles. Finally, using mathematical modeling, we illustrate how a novel dynamic feedback mechanism, “polyphasic positive feedback,” lets cells defer sporulation more robustly than with other circuit strategies. Developing techniques that can access pulsing and time-delay dynamics with higher time resolution will enable us to determine if this polyphasic strategy provides a general design principle for the regulation of multi-cell-cycle deferral times seen in other systems.
Highlights
Cells are capable of responding to stimuli extremely rapidly, on timescales of seconds or less [1]
How can cells create ‘‘timers’’ to regulate these long deferrals? We study this question in the bacterium Bacillus subtilis, which responds to stress by transforming into a dormant spore
We show that B. subtilis can defer sporulation for extended time periods by first undergoing multiple rounds of growth and proliferation, and only sporulating
Summary
Cells are capable of responding to stimuli extremely rapidly, on timescales of seconds or less [1]. Many aspects of the system remain unclear, oligodendrocyte differentiation is delayed in vivo and in cell culture, suggesting a cell-autonomous ‘‘timer’’ mechanism. Another example is the mid-blastula transition in developing Xenopus embryos, which occurs after 12 cell cycles of proliferation [3,4]. In both cases, the deferral of differentiation enables a period of proliferation preceding commitment to new fates
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