Zebrafish Gli3 Functions as Both an Activator and a Repressor in Hedgehog Signaling

Dev Biol. 2005 Jan 15;277(2):537-56. doi: 10.1016/j.ydbio.2004.10.003.

Abstract

Hedgehog (Hh) signaling regulates cell differentiation and patterning in a wide variety of embryonic tissues. In vertebrates, at least three Gli transcription factors (Gli1, Gli2, and Gli3) are involved in Hh signal transduction. Comparative studies have revealed divergent requirements for Gli1 and Gli2 in zebrafish and mouse. Here, we address the question of whether Gli3 function has also diverged in zebrafish and analyze the regulatory interactions between Hh signaling and Gli activity. We find that zebrafish Gli3 has an early function as an activator of Hh target genes that overlaps with Gli1 activator function in the ventral neural tube. In vitro reporter analysis shows that Gli3 cooperates with Gli1 to activate transcription in the presence of high concentrations of Hh. During late somitogenesis stages, Gli3 is required as a repressor of the Hh response. Gli3 shares this repressor activity with Gli2 in the dorsal spinal cord, hindbrain, and midbrain, but not in the forebrain. Consistently, zebrafish Gli3 blocks Gli1-mediated activation of a reporter gene in the absence of Hh in vitro. In the eye, Gli3 is also required for proper ath5 expression and the differentiation of retinal ganglion cells (RGCs). These results reveal a conserved role for Gli3 in vertebrate development and uncover novel regional functions and regulatory interactions among gli genes.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Differentiation / physiology
  • Central Nervous System / embryology
  • Central Nervous System / metabolism
  • Cluster Analysis
  • DNA Primers
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Eye / metabolism
  • Gene Expression Regulation, Developmental*
  • Growth Substances / metabolism
  • Hedgehog Proteins
  • In Situ Hybridization
  • Kruppel-Like Transcription Factors
  • Microinjections
  • Molecular Sequence Data
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oligonucleotides, Antisense
  • Polymorphism, Single-Stranded Conformational
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Zebrafish / embryology*
  • Zebrafish / metabolism
  • Zebrafish Proteins / metabolism
  • Zinc Finger Protein Gli3

Substances

  • DNA Primers
  • DNA-Binding Proteins
  • GLI3 protein, human
  • Growth Substances
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Oligonucleotides, Antisense
  • Trans-Activators
  • Transcription Factors
  • Zebrafish Proteins
  • Zinc Finger Protein Gli3
  • atoh7 protein, zebrafish