Dally and Notum regulate the switch between low and high level Hedgehog pathway signalling.

Area of Science:

• Developmental Biology
• Cell Signaling
• Molecular Mechanisms

Background:

• Secreted morphogens like Hedgehog (Hh) regulate cell fate and proliferation during development.
• Precise sensing of morphogen levels is critical for morphogenesis, but molecular mechanisms remain unclear.
• Hedgehog (Hh) reception involves a multi-protein complex with complex cell-surface sensing.

Purpose of the Study:

• To investigate the role of the proteoglycan Dally in Hedgehog (Hh) signaling.
• To elucidate the molecular mechanisms of Hh sensing at the cell surface.
• To understand how Dally influences Hh pathway activity levels.

Main Methods:

• Investigated Dally expression in Hh-receiving cells in Drosophila.
• Assessed Dally's necessity for high-level versus low-level Hh pathway activity.
• Examined the role of Dally's glycosyl-phosphatidyl-inositol (GPI) moiety and Notum activity in Hh internalization.

Main Results:

• Dally expression is essential for high-level, but not low-level, Hh pathway activity in Hh-receiving cells.
• Dally sequesters Hh at the cell surface and promotes its internalization with the receptor.
• Hh internalization is dependent on Notum activity and Dally's GPI moiety, distinguishing its role from Dally-like.

Conclusions:

• Dally plays a critical role in modulating Hh signaling strength.
• Hydrolysis of Dally-GPI by Notum acts as a switch, promoting Hh-Patched complex internalization and transitioning from low to high signaling levels.
• This mechanism provides new insights into the regulation of morphogen-directed morphogenesis.