TNF-α-mediated feedback loops in the control of ADPKD onset. a. Pathway diagram of the proteins and network involved in cytogenesis. b. Simulation of time courses of primary network components in the wild-type case. Random (Gaussian) noise is added to the expression level of each polycystin allele. Random fluctuations are damped because the expression noise in the two genes is uncorrelated. c. Heterogeneous background simulation. The level of polycystin is lower and the fluctuations are higher. d. Heterogenous background simulation, but with the TNF-α feedback loop disabled. Random fluctuations allow cyst formation to occur, but these are suppressed as soon as above-threshold expression of TNF-a is restored.