Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling.
Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling in vertebrates. The question remains unanswered, however, as to how these Gli proteins participate in the Shh signaling pathway. In this study, regulatory 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 domains. In cultured cells, truncation of the activation domain in the C-terminal half results in a protein with repressor activity, while removal of the repression domain at the N terminus converts Gli2 into a strong activator. In transgenic mouse embryos, N-terminally truncated Gli2, unlike the full length protein, activates a Shh target gene, HNF3beta, in the dorsal neural tube, thus mimicking the effect of Shh signal. This suggests that unmasking of the strong activation potential of Gli2 through modulation of the N-terminal repression domain is one of the key mechanisms of the Shh signaling. 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 notochord is received by the neural plate, the widely expressed Gli2 and Gli3 proteins are presumably converted to their active forms in the ventral cells, leading to activation of transcription of their target genes, including Gli1.
Sasaki
H
H
Laboratory of Developmental Biology, Institute for Molecular and Cellular Biology, Osaka University, Suita, Osaka 565-0871, Japan. hsasaki@imcb.osaka-u.ac.jp
Nishizaki
Y
Y
Hui
C
C
Nakafuku
M
M
Kondoh
H
H
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004627:Embryonic Induction; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D009420:Nervous System / Q000196:embryology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D029867:Xenopus Proteins; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D016335:Zinc Fingers / Q000235:genetics / Q000502:physiology
D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C108003:GLI3 protein, Xenopus; C065683:GLI3 protein, human; C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D011506:Proteins; D012097:Repressor Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D029867:Xenopus Proteins; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3