Plexins promote Hedgehog signaling through their cytoplasmic GAP activity

Area of Science:

• Cellular Biology
• Developmental Biology
• Molecular Signaling

Background:

• Hedgehog signaling is crucial for embryonic and postnatal development.
• Neuropilins are known positive regulators of Hedgehog signaling.
• The role of plexins, neuropilin co-receptors, in Hedgehog signaling was unexplored.

Purpose of the Study:

• To investigate the role of plexins in Hedgehog signaling.
• To elucidate the mechanism by which plexins influence Hedgehog pathway activity.

Main Methods:

• Utilized NIH/3T3 mouse fibroblasts to study plexin function.
• Assessed Hedgehog pathway activity through loss-of-function and gain-of-function experiments.
• Examined the role of the plexin GTPase-activating protein (GAP) domain and primary cilia.
• Investigated plexin effects on GLI transcription factors.
• Analyzed plexin function in the mouse dentate gyrus.

Main Results:

• Multiple plexins were found to promote Hedgehog signaling in mouse fibroblasts.
• Loss of plexin function significantly reduced Hedgehog pathway activity.
• The catalytic activity of the plexin GAP domain is essential for promoting Hedgehog signaling.
• Constitutive activation of the GAP domain enhanced Hedgehog signaling.
• Plexins promote Hedgehog signaling at the GLI transcription factor level, requiring primary cilia.
• Plexin loss of function impaired Hedgehog pathway activation in the mouse dentate gyrus.

Conclusions:

• Plexins are novel components of the Hedgehog signaling pathway.
• Plexins positively regulate Hedgehog signaling through their GAP domain activity and interaction with primary cilia.
• These findings offer new insights into the complex regulation of Hedgehog signaling in development and adult tissues.