A New Approach to Feedback for Robust Signaling Gradients.

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; but just how this might be done is a major unanswered question. Recently extensive numerical simulations suggest that robustness of signaling gradients cannot be attained by negative feedback (of the Hill's function type) on signaling receptors but can be achieved through binding with nonsignaling receptors (or nonreceptors for short) such as heparan sulfate proteoglycans with the resulting complexes degrading after endocytosis. These were followed by a number of analytical and numerical studies in support of the aforementioned observations. However, evidence of feedback regulating signaling gradients has been reported in literature. The present paper undertakes a different approach to the role of feedback in robust signaling gradients. The overall goal of the project is to investigate the effectiveness of feedback mechanisms on ligand synthesis, receptor synthesis, nonreceptor synthesis, and other regulatory processes in the morphogen gradient system. As a first step, we embark herein a proof-of-concept examination of a new spatially uniform feedback process that is distinctly different from the conventional spatially nonuniform Hill function approach.