St. Jude Children's Research Hospital scientists announced on July 27 that they have uncovered a regulatory mechanism for signaling of Sonic Hedgehog, a pathway essential for embryonic development. The research team found that the lipid arachidonic acid enhances the activity of Smoothened, a protein relaying Sonic Hedgehog signals inside cells, through a newly discovered binding site that changes the receptor's behavior and increases its signaling activity. Disrupting this interaction was shown to impair heart and lung development, highlighting how precise control of Sonic Hedgehog signaling guides tissue formation.
The findings were published in Nature Communications and provide insight into how this pathway may be modulated in diseases such as cancer. The Sonic Hedgehog pathway plays an important role during development by providing instructions that help cells determine their identity and organize into tissues. When this signaling is disrupted, it can contribute to developmental disorders including congenital heart defects and abnormalities affecting the brain, as well as cancers such as medulloblastoma.
At the center of this pathway is Smoothened, which relays signals from the cell surface to cellular machinery controlling gene activity and responses. The study builds on previous work from Ogden's lab identifying cPLA2α as a regulator of Sonic Hedgehog signaling; cPLA2α produces arachidonic acid, which boosts Smoothened activity.
Researchers discovered that arachidonic acid binds to a specific regulatory site on Smoothened where it amplifies response to Sonic Hedgehog signaling. "Arachidonic acid doesn't turn Smoothened on or off," said Ogden. "Instead, it binds to the protein and helps activated Smoothened amplify its normal response during tissue development. That extra level of control appears to be especially important in tissues, including the heart and lungs." Disrupting this regulatory mechanism reduced activation of Smoothened and impaired cardiopulmonary development but did not affect nervous system development despite the importance of this pathway there.
"Congenital heart defects represent one of the most common and severe developmental disorders, and our findings suggest that this mechanism of Smoothened signal control plays a particularly important role in heart and lung development," said Ogden. "Understanding this process could help guide strategies to modulate this pathway in specific contexts while minimizing effects on other tissues."
