Research Article

Secreting and Sensing the Same Molecule Allows Cells to Achieve Versatile Social Behaviors

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Science  07 Feb 2014:
Vol. 343, Issue 6171, 1242782
DOI: 10.1126/science.1242782

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Structured Abstract


Cells that simultaneously secrete and sense the same signaling molecule are ubiquitous. Bacteria sense a quorum by secreting and sensing an autoinducer; T cells induce a monoclonal immune response by secreting and sensing a cytokine; and epithelial cells can become cancerous through misregulated secreting and sensing of a growth factor. Many of these cells use the same core signaling-circuit motif to realize a diverse repertoire of biological functions. The full range of functions that the “secrete-and-sense” circuit motif can achieve, and the design principles underlying its functional flexibility, remain poorly understood.

Embedded Image

From circuits to multicellular behaviors: a bottom-up synthesis of hierarchy. The secrete-and-sense circuit controls how each cell (yellow circle) communicates through a signaling molecule (orange circle), which in turn controls the cell-to-cell communication. The collection of cell-to-cell communication in all pairs of cells yields population-level behaviors such as an isogenic population of secrete-and-sense cells bifurcating into two functionally distinct subpopulations (yellow and green circles).


We constructed a synthetic secrete-and-sense circuit motif in budding yeast that enabled the yeast to secrete and sense the mating pheromone. We systematically altered key parameters of the circuit—secretion rate, receptor abundance, positive feedback linking sensing with secretion, and signal degradation—to reveal how they enabled various cellular behaviors. Through single-cell measurements, we assessed the degree to which a secrete-and-sense cell responded to its own secreted signal (self-communication) versus the signal secreted by its neighbors (neighbor communication) to achieve diverse cellular behaviors.


We show that the core secrete-and-sense circuit motif can precisely tune the cell’s “sociability”—the cell’s degree of self- versus neighbor communication—using one molecule and receptor pair. At the extremes, the circuit enables purely social behaviors (e.g., quorum sensing) in which cells mainly use neighbor communication, or purely asocial behaviors (e.g., epidermal growth factor signaling in epithelial cells) in which cells mainly use self-communication, commonly referred to as “autocrine signaling.” Crucially, we uncover rich behaviors that rely on simultaneous self- and neighbor communication, including some that have been observed in nature but whose mechanistic origins have been unclear. For example, positive feedback that links sensing with secretion can yield a bistable behavior in which all cells in the population act as an ensemble to be either quiescent or maximally activated. Incorporation of an active signal degradation enables bimodal activation, in which the different proportions of the population bifurcate into distinct activation states, with the ratio of the two states determined by simultaneous self- and neighbor communication. This behavior explains how isogenic cells can differentiate into distinct states with defined ratios.


We integrate simple models, single-cell measurements, and a bottom-up synthetic biology approach to reveal a range of population-level behaviors that arise from the core secrete-and-sense circuit motif. We determine how the intracellular circuit elements result in distinct classes of self- and neighbor communication, and in turn leads to various population-level behaviors. Our work reveals “phase diagrams” that summarize the relationship between the circuit architecture and different phases of population-level behaviors for the secrete-and-sense circuit. Our first-principles approach may be generalized to reveal relationships between the structures of other fundamental cell-signaling circuits and the multicellular behaviors that they enable.

The Message in the Medium

What is the point of autocrine signaling in which a cell produces a signal that activates receptors on its own cell surface? An internal signal seems simpler, unless there is value to allowing neighboring cells to know what other cells are up to. Youk and Lim (p. 10.1126/science.1242782; see the Perspective by Lee and You) explored the broad range of signaling outcomes that can result in a system in which some yeast cells could secrete and sense a signal whereas others could only sense signals from their neighbors. The cells were engineered so that the response of the two cell types could be distinguished from one another. Experiments and mathematical modeling showed that depending on how circuits were constructed—for example, how much receptor was present, how the signal molecule was degraded, the presence of feedback, the density of the cell culture, and so on—a range of behaviors was possible: Some conditions favored activation of one type of cell over another. Others altered the timing or consistency of the response within a population. The principles revealed could also be used in other biological contexts or in the design of synthetic biological cell systems with desired regulatory properties.


Cells that secrete and sense the same signaling molecule are ubiquitous. To uncover the functional capabilities of the core “secrete-and-sense” circuit motif shared by these cells, we engineered yeast to secrete and sense the mating pheromone. Perturbing each circuit element revealed parameters that control the degree to which the cell communicated with itself versus with its neighbors. This tunable interplay of self-communication and neighbor communication enables cells to span a diverse repertoire of cellular behaviors. These include a cell being asocial by responding only to itself and social through quorum sensing, and an isogenic population of cells splitting into social and asocial subpopulations. A mathematical model explained these behaviors. The versatility of the secrete-and-sense circuit motif may explain its recurrence across species.

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