Until now, the fly and mammalian work had taken very different courses. Mammalian researchers concentrated on distal (i.e., near the fingers) FGF as a source of graded signals. But fly researchers felt that the key molecules were Wingless (Wg) and Decapentaplegic (Dpp), which are made in two stripes that intersect at the center of the area that will become a leg. (Fly larvae set up leg patterns in imaginal discs, flat layers of cells that later telescope out to form a limb.) Wg and Dpp act directly to turn on Distalless (Dll) and dachsund (dac), critical genes for leg formation. “Everyone assumed that if both of these were directly regulated, everything else must be as well,” says Campbell.
Both research teams found, however, that the Wg/Dpp signals were no longer required once Dll expression was established. Expression of later patterning genes was instead dependent on Vein (Vn) and other ligands for the EGF receptor (EGFR). Vn is made where Wg and Dpp intersect at the center of imaginal disc, and thus could act as a source of graded signals akin to FGF. Campbell, in particular, showed that different levels of EGFR activity led to activation of different downstream genes, although Couso disputes a subset of these results.
FGF- and the EGF-related ligands both activate receptor tyrosine kinases and Ras, but the direct relationship between flies and mammals remains a stretch. “I cannot say they are homologous,” says Couso. Campbell notes that the pathways may have skipped in and out of appendage development during evolution as they were co-opted for other functions. For now, he says, only one thing is sure: “You have to be very careful when you are dealing with all this evolutionary stuff.” ▪