GLI1, which encodes a member of the Gli-Kruppel family of transcription factors, was initially identified as an amplified gene and potential oncogene in a human glioblastoma (Kinzler

GLI1, which encodes a member of the Gli-Kruppel family of transcription factors, was initially identified as an amplified gene and potential oncogene in a human glioblastoma (Kinzler et al., 1987). A family of Gli genes that includes Gli1, Gli2 and Gli3 was cloned from human and mouse, and found to be expressed in many organs during mouse development (Ruppert et al., 1988; Hui et al., 1994). The fly homolog of Gli, Cubitus interruptus (Ci), is involved in mediating all Hedgehog (Hh) signaling (Methot and Basler, 2001). Given that Hh proteins are critical for many developmental processes in vertebrates, considerable effort has been made in the past decade to elucidate the function of each of the Gli genes in the Hh pathway (for reviews, see Matise and Joyner, 1999; Ingham and McMahon, 2001). In particular, the roles of the Gli proteins downstream of Sonic Hedgehog (Shh) signaling have been studied in ventral patterning of the nervous system. In fly, Hh regulates Ci function by inhibiting processing of Ci into a repressor protein, and at the same time potentiating the full-length activator protein (Aza-Blanc et al., 1997; Ohlmeyer and Kalderon, 1998; Methot and Basler, 1999). Gli2 and Gli3, but not Gli1, have been similarly found to have an N-terminal repressor domain and be cleaved into a repressor form (Dai et al., 1999; Sasaki et al., 1999; Aza-Blanc et al., 2000; Wang et al., 2000). Gli2 and Gli3 also have been found to be required for development and Shh signaling. Loss of Gli2 function results in defective Shh signaling in the floorplate of the neural tube and other tissues (Mo et al., 1997; Ding et al., 1998; Matise et al., 1998), indicating Gli2 is an activator in the Hh pathway. By contrast, loss of mouse Gli3 results in dorsal brain defects and limb polydactyly that are associated with ectopic activation of the Shh pathway (Hui and Joyner, 1993; Masuya et al., 1995; Buscher et al., 1997). The Gli3 mutant phenotype suggests that Gli3 functions primarily as a repressor in the Shh pathway. Indeed, biochemical studies have shown that Shh functions to inhibit the formation of the repressor form of Gli3 (Wang et al., 2000), and removal of Gli3 function in Shh mutants largely rescues the Shh mutant defects, showing that part of the Shh mutant phenotype is due to an excess of Gli3 repressor (Litingtung and Chiang, 2000). Interestingly, gain-of-function studies in mouse and frog embryos have shown that Gli1, but not Gli2 or Gli3, can mimic Shh function by inducing proliferation and activating Shh 4753 Development 129, 4753-4761 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV4644