Cell‐type specific utilization of multiple negative feedback loops generates developmental constancy

Abstract

Signaling pathways generally contain multiple negative regulators that are induced by the signal they repress, constructing negative feedback loops. Although such negative regulators are often expressed in a tissue-or cell-type specific manner during development, little is known about the significance of their differential expression patterns and possible interactions. We show the role and interplay of two cell-type specific negative feedback loops during specification of photoreceptor neurons in the Drosophila compound eye, a process that occurs via epidermal growth factor (EGF)-mediated sequential induction through the activation of the Ras/MAPK signaling pathway. Inducing cells secreting EGF express a negative regulator Sprouty (SPRY) that lowers Ras/MAPK signaling activity, and as a consequence reduces the signal-dependent expression of a secreted EGF inhibitor, Argos (AOS). Induced cells in turn express an orphan nuclear receptor Seven-up (SVP), which represses SPRY expression thereby allowing expression and secretion of AOS, preventing further induction. When this intricate system fails, as in spry mutants, sequential induction is no longer constant and the number of photoreceptor neurons becomes variable. Thus, cell-type specific utilization of multiple negative feedback loops not only confers developmental robustness through functional redundancy, but is a key component in generating consistent patterning.

On the functional diversity of dynamical behaviour in genetic and metabolic feedback systems

“…Designs with interlinked positive and negative feedback loop have been shown to exhibit performance advantages over simple negative feedback loops, such as the ability to easily tune frequency of oscillators, improved robustness and reliability, even under noisy environments [ 22 , 27 , 50 ]. Multiple-negative-feedback-loop designs have also been shown to enhance system robustness and generates developmental constancy [ 8 , 27 , 47 , 51 ]. We obtained in this study a number of results which further our understanding into the dynamics of coupled-loop systems.…”

Pattern formation in the Drosophila eye disc

“…Although mosaic studies suggest that Aos can act over a range of about 10 cell diameters (Freeman et al , 1992b), mathematical modeling of Aos function in the embryo indicates that Aos could exert a long-range effect by acting as a ligand sink, without itself diffusing over a long distance (Reeves et al , 2005). Interestingly, a second negative feedback loop involving the intracellular inhibitor Sprouty subsequently turns off aos expression in R8, 2 and 5; aos is maintained in other photoreceptors because sprouty expression is inhibited by the transcription factor Seven-up (Svp) expressed in these cells (Iwanami et al , 2005). This reduction in Aos production may allow Spi levels to increase sufficiently to induce the later differentiating cell types.…”

Overexpression of Spry1 in chondrocytes causes attenuated FGFR ubiquitination and sustained ERK activation resulting in chondrodysplasia

“…The Spry family functions as feedback inhibitors of the FGFR-activated ERK pathway at or proximal to Raf1 in many cell types (Furthauer et al, 2002;Hanafusa et al, 2002;Iwanami et al, 2005;Yang et al, 2006). To examine whether overexpression of mSpry1 in chondrocytes regulates ERK signaling mediated by FGFR activation in a similar manner, we employed immunofluorescence microscopy on E16.5 humerus sections using phospho-Mek1/2 antibodies ( Figure 9A).…”