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Inhibitory Gli3 activity negatively regulates Wnt/beta-catenin signaling

Fausto Ulloa1, Nobue Itasaki, James Briscoe

  • 1Developmental Neurobiology, National Institute for Medical Research, Mill Hill, London, United Kingdom.

Current Biology : CB
|March 3, 2007
PubMed

Insights

Hedgehog (Hh) and Wingless (Wnt) signaling pathways interact during embryonic development. Repressor forms of Gli3 (Gli3R), generated without Hh signaling, inhibit Wnt signaling by antagonizing beta-catenin, revealing a novel crosstalk mechanism.

Area of Science:

  • Developmental Biology
  • Molecular Signaling
  • Cellular Homeostasis

Background:

  • Hedgehog (Hh) and Wingless (Wnt) are crucial secreted signaling molecules in embryonic development and tissue maintenance.
  • In the neural tube, Wnt and Shh signaling are proposed to regulate neural progenitor proliferation and survival.
  • Shh signaling is unexpectedly vital for cell growth and survival in both ventral and dorsal neural tube regions.

Purpose of the Study:

  • To investigate the relationship between Shh signaling inhibition and Wnt-mediated transcriptional activation.
  • To elucidate the role of Gli3 in the crosstalk between Hh and Wnt pathways.
  • To understand the mechanism by which Hh signaling influences Wnt pathway activity.

Main Methods:

  • Inhibition of Shh signaling in embryonic assays and cell lines.
  • Analysis of Wnt-mediated transcriptional activation.
  • Investigation of Gli3 repressor form (Gli3R) activity.
  • Assessment of Gli3R interaction with beta-catenin.

Main Results:

  • Inhibition of Shh signaling led to decreased Wnt-mediated transcriptional activation.
  • This reduction was dependent on the Gli3 protein.
  • Gli3 repressor forms (Gli3R) were found to inhibit canonical Wnt signaling.
  • Gli3R antagonizes active beta-catenin and physically interacts with its carboxy-terminal domain.

Conclusions:

  • Gli3 repressor forms mediate crosstalk between Hh and Wnt signaling pathways.
  • Gli3R inhibits Wnt signaling by antagonizing beta-catenin.
  • This interaction provides an explanation for proliferative defects observed in Shh null embryos.

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