Sortilin regulates sorting and secretion of Sonic hedgehog

Area of Science:

• Molecular Biology
• Developmental Biology
• Cell Biology

Background:

• Sonic Hedgehog (Shh) is a crucial secreted morphogen regulating embryonic development and tissue patterning.
• The active N-terminal fragment (ShhN) is generated by autocleavage and is targeted for secretion.
• Understanding Shh transport mechanisms is vital for deciphering developmental processes.

Purpose of the Study:

• To identify novel receptors involved in Sonic Hedgehog (Shh) trafficking.
• To elucidate the role of sortilin (Sort1) in Shh processing and secretion.
• To investigate the impact of Sort1 on Shh-dependent developmental functions.

Main Methods:

• Coimmunoprecipitation and proximity ligation assays to confirm Sort1-Shh interaction.
• Cellular localization studies using immunofluorescence microscopy (Golgi colocalization).
• Functional assays in cell culture and mouse models to assess Shh secretion, patterning defects, and axonal transport.

Main Results:

• Sortilin (Sort1) was identified as a novel Shh trafficking receptor.
• Sort1 and Shh interact and colocalize at the Golgi apparatus.
• Sort1 overexpression reduces Shh secretion and alters Shh distribution.
• Loss of Sort1 partially rescues Shh processing defects and improves Hedgehog-associated patterning.
• Sort1 negatively regulates Shh anterograde transport in axons and Hedgehog-dependent axon-glial interactions.

Conclusions:

• Sortilin functions as a Shh trafficking receptor within the Golgi.
• Sort1 diverts Shh from secretory pathways, influencing its biological activity.
• Sort1 plays a regulatory role in Shh-mediated developmental patterning and neural development.