Editors' ChoiceDevelopment

Getting the Best from a Gradient

Science Signaling  27 Jan 2009:
Vol. 2, Issue 55, pp. ec28
DOI: 10.1126/scisignal.255ec28

Varied responses to gradients of the concentration of morphogens are thought to allow cells to determine their relative position in a developing organism and thus to adopt the appropriate cell fate. Although there is substantial experimental support for this idea, morphogen gradients are proposed to provide only a minimal amount of information, perhaps not enough to enable robust formation of complex developmental patterns. Piddini and Vincent explored the development of the wing in Drosophila, a process dependent on a gradient of the morphogen Wingless (Wg), and provide evidence for a further layer of regulation. Tricky genetic techniques available in the fruit fly model system allowed the authors to progressively deplete wg-expressing cells in developing wing. The authors were surprised to find that the wings looked nearly normal and expression of the distalless (dll) and vestigial (vg) genes, which is enhanced by low concentrations of Wg, continued, even in the absence of Wg signaling. In flies in which small patches of mutant cells that could not transduce Wg signals were interspersed with normal cells (rather than all of the cells in the whole imaginal disc having impaired Wg signaling), expression of dll and vg did require continued signaling by Wg. Thus, the authors reasoned that cells only need continued presence of Wg to express Wg target genes when they are surrounded by wild-type cells. This indicates that cells receiving Wg signals might produce a signal that inhibits Wg signaling in their neighbors—a process known as lateral inhibition, which can enhance contrast at the edges of regions of cells responding to a gradient of signaling. Indeed, when Wg signaling was overactivated in groups of cells, these cells suppressed dll expression in adjacent cells. The inhibitory effect of overstimulated Wg signals required the presence of Notum (also called Wingful), an inhibitor of Wg signaling that is known to be produced in cells near the source of Wg production. Furthermore, cells away from the dorsal-ventral boundary where Wg is produced appeared to produce another inhibitory signal, which has not yet been identified. Bristles are normally produced only in the region of high Wg signaling near the source of the Wg gradient, but in adult wings in which groups of cells failed to respond to Wg (and thus didn’t produce inhibitor), Wg signaling in adjacent cells was excessive and bristles formed in inappropriate places. Thus, in the absence of lateral inhibition, cells appear to misread their position in the gradient because the missing inhibitory signals from neighboring cells fail to enforce the normal sharp boundary of bristle formation.

E. Piddini, J.-P. Vincent, Interpretation of the Wingless gradient requires signal-induced self-inhibition. Cell 136, 296–307 (2009). [PubMed]