Control of tissue homeostasis, tumorigenesis, and degeneration by coupled bidirectional bistable switches
Fig 3
Tissue homeostasis is regulated by YAP/TAZ/LATS negative feedback loop.
(A) Nullcline analysis of the regulatory system shows one stable steady state (tissue homeostasis, green circle) at the intersections of the nullclines under basal parameter set. The [L]-nullcline is drawn in blue and the [YTup]-nullcline is drawn in red. The vector field of the system is represented by small arrows, where the color is proportional to the field strength. Example trajectories starting from different initial states were shown to represent the dynamics of the system towards the tissue homeostatic state. (B) The time course of the [YTup] level with the system starting from a range of initial conditions. (C) The parameter kYTup3, characterizing the strength of the YAP/TAZ-LATS1/2 negative feedback loop, was varied from 85% to 115% (left to right), with 5% increments, of its original value to plot the 1-parameter bifurcation diagrams and show its effect on the homeostatic state. (D) Two-parameter bifurcation analysis shows how the thresholds SN1, SN2, SN3, and SN4 vary with kYTup3. The monostable homeostatic state region is labeled as Mono-H (green), and the tristable region is labeled as Tri (purple), respectively. The bistable region in which the homeostatic and tumorigenic states existed within is labeled as Bi-HT (red), while the bistable region in which the homeostatic and degenerative states existed within is labeled as Bi-HD (blue). (E) Nullcline analysis of the regulatory system shows the three stable steady states and two unstable steady states when kYTup0 is within the tristable region (between SN2 and SN4) and kYTup3 is 85% of its original value.