Examining the Neurodevelopmental Impact of Sonic Hedgehog Pathway Inhibition in Mice

Area of Science:

• Neuroscience
• Developmental Biology
• Toxicology

Background:

• Neurodevelopmental disorders (NDDs) are complex and common, necessitating identification of environmental risk factors for prevention.
• The Sonic hedgehog (Shh) signaling pathway regulates craniofacial development; its disruption can cause severe malformations and neurological deficits.
• It remains unknown if Shh pathway disruption without overt facial abnormalities can lead to subtle neurodevelopmental outcomes.

Purpose of the Study:

• To investigate the effects of prenatal Sonic hedgehog (Shh) signaling pathway disruption on neurodevelopment.
• To determine if Shh pathway inhibition, in the absence of overt facial malformations, results in subtle neurobehavioral changes.

Main Methods:

• A mouse model was developed using vismodegib, a Shh pathway antagonist, administered orally during critical developmental periods (GD4-GD12).
• Embryos and fetuses were examined for craniofacial and forebrain development.
• Adult mice underwent behavioral assessments, including rotarod, open field exploration, and fear conditioning.

Main Results:

• High-dose vismodegib (225 ppm) caused forebrain abnormalities, facial and brain malformations, and early mortality.
• Lower doses (25 and 75 ppm) did not result in observable facial or brain malformations.
• Adult mice exposed to lower doses showed improved performance on rotarod tests but no significant differences in other behavioral assays compared to controls.

Conclusions:

• Prenatal Shh pathway disruption, under these experimental conditions, did not yield significant neurobehavioral differences when craniofacial malformations were absent.
• The study suggests that Shh pathway's role in subtle neurodevelopmental outcomes without overt physical defects requires further investigation.