Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix

Area of Science:

• Developmental Biology
• Cell Signaling
• Molecular Biology

Background:

• The Hedgehog (Hh) protein family plays critical roles in metazoan development.
• Hh proteins undergo lipid modifications (cholesterol and palmitate) that influence their function.
• Understanding Hh signaling dynamics is key to deciphering developmental processes.

Purpose of the Study:

• To investigate the role of lipid modifications in Hh protein spreading and reception.
• To determine how lipid modifications affect Hh pathway activation thresholds.
• To elucidate the mechanisms of Hh internalization and extracellular transport.

Main Methods:

• Utilized Drosophila wing imaginal disc as a model system.
• Compared the behavior of lipid-unmodified Hh versus wild-type Hh.
• Investigated Hh internalization pathways using dynamin-dependent mechanisms.
• Assessed the role of heparan sulfate proteoglycans (HSPG) in Hh signaling.

Main Results:

• Lipid-unmodified Hh spreads further than wild-type Hh, activating only low-threshold responses.
• Unlipidated Hh is internalized via the apical plasma membrane, while wild-type Hh uses the basolateral surface.
• Lipid-modified Hh interaction with HSPG is essential for precise epithelial spreading and full pathway activation.
• Hh-lipid modifications and HSPG are not required for activating low-level Hh response targets.

Conclusions:

• Lipid modifications on Hh proteins are vital for controlled extracellular spreading and reception.
• The interaction between lipid-modified Hh and HSPG is critical for accurate signaling across epithelial surfaces.
• Distinct mechanisms govern the activation of low versus high threshold Hh responses.