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Control of neurite growth and guidance by an inhibitory cell-body signal
Fig 3
Signalling networks for neurite growth and gradient sensing.
Activating (A) and inhibitory (I) signalling pathways are stimulated in parallel by NGF at the growth cone c1, and within the ganglion c2. By sensing an asymmetry in concentrations between growth cone and cell body, an extracellular gradient can be detected. (A) Model 1: growth. The signals are integrated by conversion of a substrate G to a growth promoting active form G*. (B) The steady-state output of the growth model, (
, black line, normalised by maximum value) reproduces the biphasic ganglion outgrowth response in uniform concentrations (c1 = c2), and saturating dissociated cell response (c2 = 0, dotted line). Black squares are data replotted from Fig 1C, normalised by the maximum outgrowth at 0.3 nM. Due to these two constraints, the network lacks the sensitivity for gradient detection. The model response with a 50% asymmetry in inputs (c1 = 1.5c2, c2 defined by the x-axis; red line) shows only a small increase over the uniform condition. Parameters: k0 = 1, k1 = 100, k2 = 0.75 and KI = 5 nM. (C) Model 2: gradient detection. Signal integration occurs through intermediaries X and Y that convert a protein F to an active form F*. Dual negative regulation from an interaction between A and I yields a sensitive readout of the ratio c1/c2 in the steady-state output. (D) Gradient detection is robust to parameter perturbations for concentrations of 0.001 − 1 nM. For each pair (c1, c2), the average response over 100 trials with noisy parameters is shown. An output of 
indicates the ‘decision’ that c1 = c2, 
indicates c1 > c2, and 
indicates c1 < c2. Parameters as described in Methods.
doi: https://doi.org/10.1371/journal.pcbi.1006218.g003