Non-receptors, Feedback, and Robust Signaling Gradients in Biological Tissue Patterning
The present dissertation is concerned with robust signaling gradients in biological tissue patterning. The patterning of many developing tissues is orchestrated by gradients of morphogens through a variety of elaborate regulatory interactions. Such interactions are thought to make gradients robust, that is, resistant to changes induced by genetic or environmental perturbations. A variety of inhibitors for reducing ectopic signaling activities are known to exist and their specific role in down-regulating the undesirable ectopic activities reasonably well established. However, how a developing organism manages to adjust inhibition/stimulation in response to genetic and/or environmental changes is still not understood. The need to adjust for ectopic signaling activities requires the presence of one or more feedback mechanisms to stimulate the needed adjustment.
Recently extensive numerical simulations suggest that robustness of the signaling gradient cannot be attained by negative feedback (of the Hill's function type) on signaling receptors; magnitude reduction of signaling gradients achieved through adequate non-signaling receptors mediated degradation is accompanied by gradient shape distortion rendering development non-robust; adequate nonreceptor-mediated degradation and commensurate negative feedback on receptor synthesis lead to robustness, but with robustness sensitive to additional up- or down-regulations of non-receptors.
Since the ultimate effect of many inhibitors (including those of the non-receptor type) is generally to reduce the availability of signaling morphogens for binding with signaling receptors, we begin our examination of possible mechanisms for achieving robust development by investigating a spatially uniform negative feedback on signaling morphogen synthesis rate. Our findings on the effectiveness of such feedback adjustments as well as similar feedback mechanisms on receptor and non-receptor syntheses both in steady state and during transient development will be discussed to provide a simpler theoretical explanation of the results from numerical simulations.