The Inseparable Relationship Between Cholesterol and Hedgehog Signaling.

Area of Science:

• Developmental Biology
• Molecular Biology
• Cell Biology

Background:

• Hedgehog (HH) pathway ligands are crucial paracrine signaling molecules coordinating metazoan tissue development.
• Cholesterol plays a recurring role in HH signaling, from ligand creation to cellular reception.

Purpose of the Study:

• To elucidate the multifaceted role of cholesterol in Hedgehog (HH) pathway signaling.
• To understand how cholesterol facilitates HH ligand secretion, dispersal, and reception.

Main Methods:

• Analysis of HH ligand biogenesis and secretion mechanisms.
• Investigation of cholesterol's role in HH signal transduction across the plasma membrane.
• Examination of the signaling circuit involving cholesterol transporters and sensors.

Main Results:

• A covalently attached cholesterol molecule acts as a molecular baton, directed by transfer proteins for HH ligand transport.
• A specific signaling circuit, including a cholesterol transporter and sensor, regulates HH signal transmission into the cytoplasm.
• The repeated involvement of cholesterol suggests HH pathway evolution through co-option of ancient lipid regulation systems.

Conclusions:

• Cholesterol is indispensable for multiple stages of HH pathway signaling, acting as a key molecular facilitator.
• The HH pathway's reliance on cholesterol highlights its evolutionary origins in ancient sterol-lipid regulatory mechanisms.
• Understanding cholesterol's role provides insights into HH pathway function and potential therapeutic targets.