Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb.
Ci/Gli zinc finger proteins mediate the transcriptional effects of Hedgehog protein signals. In Drosophila, Ci action as transcriptional repressor or activator is contingent upon Hedgehog-regulated, PKA-dependent proteolytic processing. We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein. The resulting anterior/posterior Gli3 repressor gradient can be perturbed by mutations of Gli3 in human genetic syndromes or by misregulation of Gli3 processing in the chicken mutant talpid2, producing a range of limb patterning malformations. The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation.
Wang
B
B
Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Fallon
J F
JF
Beachy
P A
PA
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001483:Base Sequence; D019521:Body Patterning; D019556:COS Cells; D002642:Chick Embryo; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D018878:Limb Buds / Q000196:embryology*; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic; D029867:Xenopus Proteins; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
D000906:Antibodies; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C082593:GLI2 protein, human; 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; D009687:Nuclear 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; D017868:Cyclic AMP-Dependent Protein Kinases