| A bistable system is one with two distinct stable steady states; in a genetic network, these states correspond to different gene expression patterns. Bistability can result from positive feedback, in which a gene directly or indirectly stimulates its own expression. We began by studying a model, originally developed by von Dassow et al., of the genetic interactions that define the polarity of segments in the Drosophila melanogaster embryo [115]. The initial study found that the network was robust to parameter variations, but it did not explain the mechanism of this robustness. We showed that the model worked due to bistable expression of wg and en, two key segment polarity genes subject to positive feedback regulation, with the stable states corresponding to cell fates in the developmental pattern. In order to study bistability experimentally, we introduced positive feedback into the budding yeast pheromone response by expressing constitutive alleles of pathway genes from a pheromone-induced promoter. We confirmed that the resulting system was bistable, albeit subject to stochastic switching between states. We varied the strength of feedback with different promoter alleles and with chemical inhibition of the pathway and found regimes of wild-type, bistable, and constitutive activity, confirming semi-quantitative theoretical predictions. We also showed directly that the active stable state depends on positive feedback. |
