Examining the Neurodevelopmental Impact of Sonic Hedgehog Pathway Inhibition in Mice

Neurodevelopmental disorders (NDDs) are common, highly variable, and etiologically complex. Identifying environmental factors that adversely impact prenatal brain development is a direct path to NDD prevention. Small molecule disruption of the Sonic hedgehog (Shh) signaling pathway, a key regulator of craniofacial morphogenesis, can lead to overt face and forebrain malformations that produce profound neurological deficits. However, whether environmental disruption of Shh signaling can cause subtle neurodevelopmental outcomes in the absence of overt facial malformations was unknown.

We developed a dietary model of Shh signaling inhibition using the specific Shh pathway antagonist vismodegib. C57BL/6J mice were fed control chow or chow containing 25, 75, or 225 ppm vismodegib from gestational day (GD)4 through GD12 to target Shh signaling during craniofacial morphogenesis. Impacts of Shh pathway disruption on face and forebrain development were examined in exposed embryos and fetuses, and behavioral characteristics were assessed in adult mice.

Exposure to chow containing 225 ppm vismodegib resulted in abnormal forebrain patterning at GD11, face and brain malformations at GD17, and early postnatal mortality, while lower treatment groups appeared phenotypically normal. Adult mice exposed to 25 and 75 ppm vismodegib outperformed control mice on repeated rotarod sessions, but treated mice did not significantly differ from control animals in open field exploration, marble burying, olfactory discrimination and detection, or fear conditioning assays.

Under the examined conditions, prenatal Shh disruption did not produce robust neurobehavioral differences in the absence of craniofacial malformations.