The vertebrate central nervous system is organized into and Hidalgo, 1993). Either loss of Ptc or too much Hh functional units dedicated to specific tasks such as the leads to ectopic transcription of the wingless (wg) gene, detection of form and of movement. Understanding the which encodes a secreted Wnt-class signal that controls embryogenesis of these patterns is a daunting task, but cell fates. Thus, hh normally maintains wg transcription it has been aided greatly by genetic studies in model in a limited region, and ptc normally represses wg outorganisms such as the fruit fly Drosophila. The strength side that region. Despite the gross patterning defects of this approach is exemplified by the Hedgehog (Hh) observed in ptc mutant embryos, no change in cell divisignaling system, initially identified in flies and subsesion frequency or pattern has been noted (Martinez Arias quently found to play an essential role in human neural et al., 1988). development and disease. Misregulation of Hh signaling In contrast, during imaginal disc development, Hh sigin humans is associated with mental retardation and naling strongly affects both cell fate and growth. Cells gross neural tube defects such as spina bifida, which that lack Ptc or are exposed to high levels of Hh assume is a malformation of the spinal column, and holopro- fates of cells usually found in the central wing region sencephaly, a loss of midline structures in the brain and(Figure 1)(Phillips et al., 1990; Ingham and Fietz, 1995). face (Belloni et al., 1996; Hahn et al., 1996b; Johnson In addition, either ectopic expression of Hh or loss of et al., 1996; Roessler et al., 1996). In adults, the Hh Ptc function causes dramatic mirror-image duplications pathway is essential for restraining growth in the ner- or triplications in the legs and wings (Phillips et al., 1990; vous system and other tissues; mutations in pathway Basler and Struhl, 1994). In contrast, excess Ptc inhibits components lead to a variety of tumors, including basal growth, leading to small wings (Johnson et al., 1995). cell carcinoma, the most common human cancer, and Some of these effects are due to Hh induction of deca-medulloblastoma, a childhood brain tumor (Gailani et pentaplegic (dpp), a TGFß-class signal, in a stripe along al., 1996; Hahn et al., 1996b; Johnson et al., 1996; Oro the border between the anterior and posterior compartet al., 1997; Pietsch et al., 1997; Raffel et al., 1997; ments (Figure 1)(Basler and Struhl, 1994; Tabata and Unden et al., 1997; Wolter et al., 1997; Xie et al., 1997). Kornberg, 1994). Again, Ptc acts in opposition to Hh Understanding Hh signaling may lead to improved treat- and inhibits dpp transcription (Capdevila et al., 1994b; ments for these human disorders. Johnson et al., 1995). Dpp appears to be responsible for much of Hh’s long-range activity in discs (Capdevila Although “the Hh pathway” is now diagrammed in and Guerrero, 1994; Ingham and Fietz, 1995). Both Dpp many textbooks, many questions remain, not least of and Wg act as long-range signals and can cause extenwhich is how the Hh signal is sent and received. In this sivepatternrearrangementswhenmisexpressed (Nellen review, we focus on what has been learned about Hh et al., 1996; Zecca et al., 1996). Normal development signaling in the nervous system, how regulation of cell therefore depends on the ability of Hh and Ptc to restrict fate and cell division are interwoven, and what we now production of secondary signals to the right places. know about the intracellular steps in Hh signal transduc-The mutual antagonism between Hh and Ptc also contion. We begin with an introduction to two key members trols the transcription of ptc itself (Ingham et al …