The Amino-Terminal Region of Gli3 Antagonizes the Shh Response and Acts in Dorsoventral Fate Specification in the Developing Spinal Cord

Dev Biol. 2003 May 15;257(2):343-55. doi: 10.1016/s0012-1606(03)00065-4.

Abstract

A concentration gradient of Shh is thought to pattern the ventral neural tube, and these ventral cell types are absent in shh-/- mice. Based on in vitro and genetic studies, the zinc finger-containing transcription factors Gli 1, 2, and 3 are mediators of the Shh intracellular response. The floorplate and adjacent cell types are absent in gli1-/-;gli2-/- mice, but part of the Shh-/- phenotype in the neural tube is alleviated in the Shh-/-;gli3-/- double mutant. This is consistent with the predicted role of Gli3 as a repressor of the Shh response. Gli3 repressor activity is blocked by Shh. In order to test the role of the repressor form of Gli3 in the neural tube, a truncated version of Gli3 (Gli3R*) was designed to mimic a Pallister Hall allele. Gli3R* acts as a constitutive repressor independent of Shh signaling. Misexpression of Gli3R* in the chick neural tube caused a ventral expansion of class-I, dorsal progenitor proteins and a loss of class-II, ventral progenitor proteins consistent with expected activity as a repressor of the Shh response. Activation of the BMP response is sufficient to maintain gli3 expression in neural plate explants, which might be a mechanism by which BMPs antagonize the Shh response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / physiology
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Chick Embryo
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryonic Induction / physiology*
  • Eye Proteins
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Kruppel-Like Transcription Factors
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neural Tube Defects / genetics
  • Neurons / physiology
  • PAX6 Transcription Factor
  • PAX7 Transcription Factor
  • Paired Box Transcription Factors
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Spinal Cord / embryology*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Xenopus Proteins*
  • Zebrafish Proteins
  • Zinc Finger Protein Gli3

Substances

  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • Eye Proteins
  • GLI3 protein, Xenopus
  • GLI3 protein, human
  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Nkx2.2 protein
  • Nkx6-1 protein, mouse
  • PAX6 Transcription Factor
  • PAX6 protein, human
  • PAX7 Transcription Factor
  • Paired Box Transcription Factors
  • Pax6 protein, mouse
  • Peptide Fragments
  • Repressor Proteins
  • SHH protein, human
  • Trans-Activators
  • Transcription Factors
  • Xenopus Proteins
  • Zebrafish Proteins
  • Zinc Finger Protein Gli3
  • bmp4 protein, Xenopus