Memory and Bistability in the Pheromone Response Pthway Public Deposited

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Last Modified
  • March 22, 2019
Creator
  • Vered, Lior
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • Polarity is the asymmetric organization of cellular structures, and is critical for differentiation, morphogenesis and migration in all eukaryotes. Many mathematical models of polarity rely on the existence of two stable steady states, and which state is observed depends on past conditions. However, bistable regulation of polarity has yet to be proven experimentally. One of the hallmarks of a bistability is hysteresis, a mechanism of memory in which the response of a system depends on its history. To identify hysteresis, we compared the minimum pheromone concentration needed to establish polarity with the minimum concentration needed to maintain polarity. Using a method of live-cell microfluidic microscopy, we determined that the minimum pheromone concentration required to establish polarity is 6 nM. When determining the minimum pheromone concentration required to maintain polarity, we observed that during a multi-step reduction of pheromone concentration most cells continued to hold polarity and cell cycle arrest at concentrations below 6 nM. In fact, a fraction of cells (~30%) held polarity and cell cycle arrest even after pheromone was completely removed. The difference between the minimum pheromone concentration required to establish polarity (~ 6 nM), and the minimum concentration required to maintain polarity (~ 0 nM), suggests that the polarity is bistable. Surprisingly, cells will disassemble polarity rapidly after a one-step reduction in pheromone concentration to 5 nM or less. The finding that the number of steps taken to reduce the pheromone concentration determines whether cells maintain polarity is consistent with a model containing a slow-adjusting negative regulation and a fast-adjusting positive feedback. We confirmed this model by successfully testing two predictions – that whether cells lose polarity after a one-step pheromone reduction and the rate at which polarity disassembly occurs will depend on the initial pheromone concentration. Our studies have shown that pheromone regulated polarity is bistable. We also confirmed a model of slow-adjusting negative regulation and fast-adjusting positive feedback that plays a role in this mechanism of memory. The presence of bistability in pheromone regulated polarity is informative to the study of polarity in other organisms and will inform future mathematical models.
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Advisor
  • Dohlman, Henrik
  • Errede, Beverly
  • Thompson, Nancy
  • Elston, Timothy
  • Erie, Dorothy
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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