Related Experiment Video
Updated: Mar 30, 2026
Ex utero Electroporation and Whole Hemisphere Explants: A Simple Experimental Method for Studies of Early Cortical Development
Published on: April 3, 2013
An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development
Seung Tae Baek1,2, Brett Copeland1, Eun-Jin Yun3
1Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA.
Abstract:
Focal malformations of cortical development (FMCDs) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway are found in a wide range of brain diseases, including FMCDs. It remains unclear how a mutation in a small fraction of cells disrupts the architecture of the entire hemisphere. Within human FMCD-affected brain, we found that cells showing activation of the PI3K-AKT-mTOR pathway were enriched for the AKT3(E17K) mutation. Introducing the FMCD-causing mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed misexpression of reelin, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to derepression of reelin transcription in a manner dependent on the forkhead box (FOX) transcription factor FOXG1. Treatments aimed at either 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.
Insights
Somatic mutations in the PI3K-AKT-mTOR pathway cause focal malformations of cortical development (FMCDs) leading to pediatric epilepsy. Targeting this AKT-FOXG1-reelin pathway may offer new epilepsy treatments.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Focal malformations of cortical development (FMCDs) are a primary cause of drug-resistant pediatric epilepsy.
- Somatic mutations activating the PI3K-AKT-mTOR pathway are implicated in various brain disorders, including FMCDs.
- The mechanism by which limited mutations disrupt entire brain hemispheres remains unclear.
Purpose of the Study:
- Investigate the role of PI3K-AKT-mTOR pathway mutations in FMCDs.
- Elucidate how these mutations affect brain architecture and neuronal migration.
- Identify potential therapeutic targets for FMCD-related epilepsy.
Main Methods:
- Analysis of human FMCD brain tissue to identify mutation-expressing cells.
- Introduction of FMCD-causing mutations into mouse models.
- Assessment of neuronal migration defects and gene expression changes (reelin, FOXG1).
- Testing of therapeutic interventions targeting AKT signaling and reelin.
Main Results:
- AKT3(E17K) mutation identified in activated PI3K-AKT-mTOR pathway cells in human FMCDs.
- Mouse models with FMCD mutations exhibited seizures and impaired hemispheric development.
- Mutation-expressing cells showed reelin misexpression, causing non-cell autonomous migration defects dependent on FOXG1.
- Inhibition of AKT signaling or reelin restored neuronal migration.
Conclusions:
- A central AKT-FOXG1-reelin signaling pathway is implicated in FMCD pathogenesis.
- This pathway disruption leads to epilepsy and abnormal brain development.
- Inhibitors of this pathway represent potential therapeutic strategies for focal epilepsy.
