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An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development.

  • Author(s): Baek, Seung Tae;
  • Copeland, Brett;
  • Yun, Eun-Jin;
  • Kwon, Seok-Kyu;
  • Guemez-Gamboa, Alicia;
  • Schaffer, Ashleigh E;
  • Kim, Sangwoo;
  • Kang, Hoon-Chul;
  • Song, Saera;
  • Mathern, Gary W;
  • Gleeson, Joseph G
  • et al.

Published Web Location

https://doi.org/10.1038/nm.3982
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.

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