Multiple Paths to Morphogen Gradient Robustness

Much recent attention has focused on the robustness of morphogen gradients, i.e. the ability of such gradients to resist change in the face of genetic and environmental perturbations. It has been suggested that some of the complex regulatory interactions found in morphogen gradients—feedback control of morphogen responsiveness, countergradients of secreted inhibitors, etc.—exist to enhance robustness, but how this occurs is only partly understood. Here we identify two strategies that make gradients robust to changes in morphogen synthesis rate. Both utilize non-receptor cell surface molecules to mediate a substantial fraction of morphogen degradation. One exploits the non-linear, i.e. saturable, nature of binding of morphogens to receptors; the other takes advantage of feedback inhibition of receptor synthesis by morphogen signaling. Such strategies may play a role in the Decapentaplegic gradient in the Drosophila wing disc, in which just such feedback is present, and in which cell surface non-receptor molecules (e.g. proteoglycans) are known to regulate gradient shape. Introduction Highly patterned arrangements of organs and tissues arise during development because groups of cells adopt different fates depending on the their precise location in space. This process is commonly orchestrated by secreted signaling molecules known as morphogens. Morphogens diffuse (or, as proposed by some investigators, are actively transported) randomly away from their site of production to form spatial gradients. At different distances, cells experience different levels of occupancy of morphogen receptors. The resulting graded differences in signaling ultimately give rise sharp differences in gene expression, from which follow stable differences in cell fate.