H. Sasaki et al., Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling, DEVELOPMENT, 126(17), 1999, pp. 3915-3924
Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signa
ling in vertebrates. The question remains unanswered, however, as to how th
ese Gli proteins participate in the Shh signaling pathway. In this study, r
egulatory activities associated with the Gli2 protein were investigated in
relation to the Shh signaling. Although Gli2 acts as a weak transcriptional
activator, it is in fact a composite of positive and negative regulatory d
omains. In cultured cells, truncation of the activation domain in the C-ter
minal half results in a protein with repressor activity, while removal of t
he repression domain at the N terminus converts Gli2 into a strong activato
r. In transgenic mouse embryos, N-terminally truncated Gli2, unlike the ful
l length protein, activates a Shh target gene, HNF3 beta, in the dorsal neu
ral tube, thus mimicking the effect of Shh signal. This suggests that unmas
king of the strong activation potential of Gli2 through modulation of the N
-terminal repression domain is one of the key mechanisms of the Shh signali
ng, A similar regulatory mechanism involving the N-terminal region was also
found for Gli3, but not for Gli1. When the Shh signal derived from the not
ochord is received by the neural plate, the widely expressed Gli2 and Gli3
proteins are presumably converted to their active forms in the ventral cell
s, leading to activation of transcription of their target genes, including
Gli1.