Hedgehog and Patched Review in Neural Development and Disease

1989; Nakano et al., 1989) that dictates alternative developmental decisions or inhibits growth unless opposed by Hh activity. For example, in ptc mutant fly embryos, the central pattern elements of the ventral epidermis are Stanford University School of Medicine deleted and replaced with mirror-image duplications of Stanford, California 94305 the segment borders (Nü sslein-Volhard and Wieschaus, 1980; Martinez Arias et al., 1988); nearly the same phenotype is seen when hh is ubiquitously expressed (Ingham 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 out-organisms 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 divi-signaling system, initially identified in flies and subse-sion 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 sig-in 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 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 TGF␤-class signal, in a stripe …