Hippo signaling activates hedgehog signaling by Taz-driven Gli3 processing

Area of Science:

• Developmental Biology
• Molecular Biology
• Cell Signaling

Background:

• Hippo and Hedgehog signaling pathways play critical roles in biological processes and diseases.
• Understanding their interactions is essential for deciphering complex biological regulation.
• The Hippo pathway effector, Taz, is implicated in regulating Hedgehog signaling.

Purpose of the Study:

• To investigate the interaction between Hippo and Hedgehog signaling pathways.
• To elucidate the mechanism by which Hippo signaling regulates Hedgehog signaling via Taz.
• To examine the role of Taz-dependent Gli3 processing in limb development.

Main Methods:

• Analysis of gene expression patterns in mouse embryonic limb buds.
• Investigating the effect of Taz deletion on Hedgehog signaling components.
• Studying the impact of Shh deletion and Taz deletion on limb phenotypes.
• Biochemical assays to determine Taz's effect on Gli3 phosphorylation and processing.

Main Results:

• Taz activation enhances Hedgehog signaling transcriptional output.
• Taz expression gradient in limb bud mesoderm mirrors Sonic hedgehog (Shh).
• Taz promotes Protein Kinase A (PKA)-mediated phosphorylation and processing of Gli3, attenuating Hedgehog signaling independently of Shh.
• Taz deletion in mouse embryonic limb bud mesenchyme enhances Hedgehog signaling and partially rescues Shh deletion phenotypes related to anteroposterior patterning and digit development.

Conclusions:

• Taz-dependent Gli3 processing represents a novel mechanism controlling Hedgehog signaling.
• Hippo signaling cross-regulates Hedgehog signaling through Taz-mediated Gli3 processing.
• This interaction is crucial for proper limb bud anteroposterior patterning and digit formation.