Regulatory feedback on receptor and non-receptor synthesis for robust signaling.

Elaborate regulatory feedback processes are thought to make biological development robust, that is, resistant to changes induced by genetic or environmental perturbations. How this might be done is still not completely understood. Previous numerical simulations on reaction-diffusion models of Dpp gradients in Drosophila wing imaginal disc have showed that feedback (of the Hill function type) on (signaling) receptors and/or non-(signaling) receptors are of limited effectiveness in promoting robustness. Spatial nonuniformity of the feedback processes has also been shown theoretically to lead to serious shape distortion and a principal cause for ineffectiveness. Through mathematical modeling and analysis, the present article shows that spatially uniform nonlocal feedback mechanisms typically modify gradient shape through a shape parameter (that does not change with location). This in turn enables us to uncover new multi-feedback instrument for effective promotion of robust signaling gradients

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

TRANSIENT FEEDBACK AND ROBUST SIGNALING GRADIENTS.

Robust development of biological organisms in the presence of genetic and epi-genetic perturbations is important for time spans short relative to evolutionary time. Gradients of receptor bound signaling morphogens are responsible for patterning formation and development. 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 understood. However, how a developing organism manages to adjust inhibition/stimulation in response to genetic and/or environmental changes remains to be uncovered. The need to adjust for ectopic signaling activities requires the presence of one or more feedback mechanisms to stimulate the needed adjustment. As the ultimate effect of many inhibitors (including those of the nonreceptor type) is to reduce the availability of signaling morphogens for binding with signaling receptors, a negative feedback on signaling morphogen synthesis rate based on a root-mean-square measure of the spatial distribution of signaling concentration offers a simple approach to robusness and has been demonstrated to be effective in a proof-of-concept implementation. In this paper, we complement the previous investigation of feedback in steady state by examining the effect of one or more feedback adjustments during the transient phase of the biological development

TRANSIENT FEEDBACK AND ROBUST SIGNALING GRADIENTS.

Robust development of biological organisms in the presence of genetic and epi-genetic perturbations is important for time spans short relative to evolutionary time. Gradients of receptor bound signaling morphogens are responsible for patterning formation and development. 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 understood. However, how a developing organism manages to adjust inhibition/stimulation in response to genetic and/or environmental changes remains to be uncovered. The need to adjust for ectopic signaling activities requires the presence of one or more feedback mechanisms to stimulate the needed adjustment. As the ultimate effect of many inhibitors (including those of the nonreceptor type) is to reduce the availability of signaling morphogens for binding with signaling receptors, a negative feedback on signaling morphogen synthesis rate based on a root-mean-square measure of the spatial distribution of signaling concentration offers a simple approach to robusness and has been demonstrated to be effective in a proof-of-concept implementation. In this paper, we complement the previous investigation of feedback in steady state by examining the effect of one or more feedback adjustments during the transient phase of the biological development

Regulatory feedback on receptor and non-receptor synthesis for robust signaling.

Elaborate regulatory feedback processes are thought to make biological development robust, that is, resistant to changes induced by genetic or environmental perturbations. How this might be done is still not completely understood. Previous numerical simulations on reaction-diffusion models of Dpp gradients in Drosophila wing imaginal disc have showed that feedback (of the Hill function type) on (signaling) receptors and/or non-(signaling) receptors are of limited effectiveness in promoting robustness. Spatial nonuniformity of the feedback processes has also been shown theoretically to lead to serious shape distortion and a principal cause for ineffectiveness. Through mathematical modeling and analysis, the present article shows that spatially uniform nonlocal feedback mechanisms typically modify gradient shape through a shape parameter (that does not change with location). This in turn enables us to uncover new multi-feedback instrument for effective promotion of robust signaling gradients