Hedgehog-Regulated Processing of Gli3 Produces an Anterior/Posterior Repressor Gradient in the Developing Vertebrate Limb

• Published in: Cell Vol. 100; no. 4; pp. 423 - 434
• Main Authors: Wang, Baolin, Fallon, John F, Beachy, Philip A
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-02-2000
• Subjects: Animals; Antibodies - immunology; Base Sequence; Body Patterning; Chick Embryo; COS Cells; Cubitus interruptus protein; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA, Complementary; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Drosophila; Gene Expression Regulation, Developmental; Gli3 gene; Gli3 protein; Hedgehog protein; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Limb Buds - embryology; Mice; Molecular Sequence Data; Nerve Tissue Proteins; Nuclear Proteins; Phosphorylation; Protein Processing, Post-Translational; Proteins - metabolism; Repressor Proteins; Sonic hedgehog protein; Trans-Activators; Transcription Factors - genetics; Transcription Factors - immunology; Transcription Factors - metabolism; Transcription, Genetic; Xenopus Proteins; Zinc Finger Protein Gli2; Zinc Finger Protein Gli3
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)80678-9

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
talpid
2
, 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.