An AKT3-FOXG1-Reelin Network Underlies Defective Migration in Human Focal Malformations of Cortical Development

Focal malformations of cortical development (FMCD) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the PI3K-AKT-mTOR pathway are found in a wide range of brain diseases, including FMCD. It remains unclear how a mutation in a small fraction of cells can disrupt the architecture of the entire hemisphere. We show that, within human FMCD brain, cells showing activation of this pathway were enriched for the mutation. Introducing the FMCD mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed reelin misexpression, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to FOXG1-mediated de-repression of reelin transcription. Treatments aimed at blocking downstream AKT signaling or inactivating reelin restored migration. These findings suggest a central AKT-FOXG1-Reelin signaling pathway in FMCD, and support pathway inhibitors as potential treatments or therapies for some forms of focal epilepsy.