Fig. 7. Two-step model for R8 specification. (A) Our model for lateral inhibition during R8 specification proposes both activation of N in cells inhibited from R8 fate and inactivation of N in cells taking R8 fate. Notch signaling is indicated by shading. Darker shading corresponds to more intense Notch activity. The model proposes two routes for adopting non-R8 fate. In some cells, N activation by Dl is sufficient to block R8 specification. In other cells, less N activation occurs, leading to an intermediate state in which R8 specification is possible if N becomes insensitive to activation by Dl, and inhibition of R8 fate is possible if further activation of N by Dl occurs. The mechanism of desensitization is not known but might involve EGF repeat 14 of the N extracellular domain (Li et al., 2003). Sca and Gp150 promote sensitivity to Dl in such cells (or antagonize the block to Dl), allowing some cells in this intermediate state to activate N and avoid R8 specification. (B) R8 cells retain sensitivity to Dl in the spl mutant allele of N (Li et al., 2003). Such activity depends on Sca and Gp150, and is interpreted here as a shift in the equilibrium away from R8 specification back towards the intermediate state. Persistent N signaling in differentiating R8 cells is the cause of abnormalities in spl mutants (Li et al., 2003). (C) In the absence of Dl, no lateral inhibition occur and all cells competent to do so take R8 fate. (D) In the absence of Sca or Gp150, cells in the intermediate state tend to lose Dl sensitivity and take R8 fate. Two distributions of cells seem most at risk of acquiring R8 fate this way. One is cells closest to the actual R8 precursor and which have the highest probability of replacing it. The other would be cells distant from neural precursors, where the influence of Dl might be weakest and the level of N signaling lowest. In fact these are the locations where ectopic neural cells arise in sca or gp150 mutants. Supernumerary R8 and bristle precursors propose both adjacent to normal precursors and at a distance from them (Baker and Zitron, 1995). We propose that these cells have greatest need of Sca and Gp150 to promote N activity and prevent protection from Dl.