Inhibitory Gli3 Activity Negatively Regulates Wnt/-Catenin Signaling

Ulloa F. et al, Current Biology (2007)

Hedgehog Signaling

Varjosalo M. and Taipale J. JCS (2007)

• Development– Nervous System

• Disease– Cyclopia

– Holoprosencephaly

• Cancer

• Homologes of Hedgehog– Sonic hedgehog

– Indian hedgehog

– Desert hedgehog

Shh

Wnt1

Fuccillo et al. Nature Reviews Neuroscience (2006)

Sonic Hedgehog in the Neural Tube

Ventral

Dorsal

Proliferation and Survival of Neural Progenitors

• Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling. - Taylor MD. et al, Oncogene (2004)

• Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog. - Glise B. et al, Dev Cell (2005)

• Suppressing Wnt signaling by the hedgehog pathway through sFRP-1. - He J. et al, JBC (2006)

• Wnt signaling inhibitors regulate the transcriptional response to morphogenetic Shh-Gli signaling in the neural tube. - Lei O. et al, Dev Cell (2006)

• Gli1 acts through Snail and E-cadherin to promote nuclear signaling by beta-catenin. - Li X. et al, Oncogene (2007)

Hedgehog and Wnt Signaling

Wnt signaling is decreased in the absence of Shh signaling

In Shh null embryos, apoptotic cells were detected in ventral and dorsal regions.

Ptc1Δloop2 – a dominant active form inhibits Hh signaling

Gli3R Iinhibits Canonical Wnt Signaling

Gli3R Inhibits -Catenin Activity

Gli3R Inhibits -Catenin-InducedSecondary Axis Formation in Xenopus Embryos

Gli3R Interacts with -Catenin

Gli3R

In the absence of Shh signaling,

high levels of Gli3R act to inhibit Wnt signaling.

Result

sFRP-1(?)