The long and short of hedgehog signaling

The past decade has seen a revolution in our understanding of the molecular basis of embryonic development in higher organisms. As our understanding of vertebrate development has grown, a number of completely unanticipated and truly remarkable parallels between mechanisms of patterning in vertebrates and Drosophila have been revealed (Scott, 1994). These findings suggest that the wealth of genetic and molecular information available concerning fly development will continue to provide an enormous resource for gaining further insight into vertebrate development. Indeed, many significant genes known to control various aspects of fly development have vertebrate homologs. Although their developmental roles may not be specifically conserved, analysis of their function will provide clues to the general processes they control and mechanisms by which they act. The role of hedgehog (hh) genes as intercellular signals in establishing embryonic pattern provides a dramatic example of this transfer of developmental insight from Drosophila to vertebrates and shows how studies in both organisms can synergistically lead to rapid elucidation of the molecular mechanisms underlying embryological processes. One mechanism by which developing embryos attain proper position-specific cell differentiation is to organize cell fates relative to a discrete inducing tissue. In principle, such induction could be achieved by a single long-range secreted signal instructing cell fate in a concentrationdependent manner (Figure la). Molecules acting via this mechanism have been termed morphogens. Alternatively, the primary inductive response could be quite local, initiating a cascade of short-range signals that are then propagated through responding tissues (Figure 1 b). Finally, the inductive trigger could act locally to initiate long-range and graded secondary signals (Figure 1 c). The identification of hh genes as key signals in a variety of embryonic inductive processes provides an opportunity to determine which of these theoretical mechanisms are actually used in regulating pattern. Shortand Long.Range Signaling by hh hh was identified by NLisslein-Volhard and Wieschaus (1980) in a saturation screen for mutants that affect larval cuticular patterning in Drosophila. Subsequent studies have shown that hh encodes a secreted protein that plays multiple inductive roles during fly development (reviewed by Perrimon, 1995). Via short-range action, over 1 or 2-cell diameters, hh regulates aspects of embryonic segmentation and patterning of adult appendages. In establishing early segmental borders, the inductive targets of hh signaling cells are directly adjacent cells. A cascade of shortrange interactions is thereby initiated that programs cell fate at different positions within the segment, corresponding to the model diagrammed in Figure lb. In the case of appendages, hh again acts locally to pattern cells within the larval appendage anlage, the imaginal discs. In this instance, however, cells respond locally by secreting decapentaplegic (dpp), which then may serve to pattern the disc in a graded manner over considerable distances, as shown in Figure lc. Besides these short-range activities, hh also is responsible for long-range specification of cell types in the dorsal epidermis. While at times cited as evidence of long-range hh induction, this latter process could result either from a direct action of hh on both adjacent and distant cells, as shown in Figure la, or it could depend upon the secretion of a second (as yet unidentified) longrange factor, as shown in Figure lc. Vertebrate homologs of hh have been isolated in screens utilizing the cloned Drosophila gene. One homolog in particular, Sonic hedgehog (Shh), displays a surprisingly wide range of activities in vertebrate embryos (Smith, 1994). SH H regulates dorsal-ventral patterning of the neural tube, the somites, and the anterior-posterior axis of the limb bud. As with its Drosophila homolog, the Shh gene product appears to act locally in some circumstances (floor