Hedgehog-regulated Processing of Gli3 Produces an anterior/posterior Repressor Gradient in the Developing Vertebrate Limb

Cell. 2000 Feb 18;100(4):423-34. doi: 10.1016/s0092-8674(00)80678-9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / immunology
  • Base Sequence
  • Body Patterning
  • COS Cells
  • Chick Embryo
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA, Complementary
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Developmental
  • 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*
  • Trans-Activators*
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Xenopus Proteins*
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3

Substances

  • Antibodies
  • DNA, Complementary
  • DNA-Binding Proteins
  • GLI2 protein, human
  • GLI3 protein, Xenopus
  • GLI3 protein, human
  • Gli2 protein, mouse
  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Proteins
  • Repressor Proteins
  • SHH protein, human
  • Trans-Activators
  • Transcription Factors
  • Xenopus Proteins
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3
  • Cyclic AMP-Dependent Protein Kinases

Associated data

  • GENBANK/AF222990