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

Seung Tae Baek, Brett Copeland, Eun Jin Yun, Seok Kyu Kwon, Alicia Guemez-Gamboa, Ashleigh E. Schaffer, Sangwoo Kim, Hoon Chul Kang, Saera Song, Gary W. Mathern, Joseph G. Gleeson

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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 AKT3E17K 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.

Original languageEnglish
Pages (from-to)1445-1454
Number of pages10
JournalNature Medicine
Volume21
Issue number12
DOIs
Publication statusPublished - 2015 Dec 1

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Baek, S. T., Copeland, B., Yun, E. J., Kwon, S. K., Guemez-Gamboa, A., Schaffer, A. E., Kim, S., Kang, H. C., Song, S., Mathern, G. W., & Gleeson, J. G. (2015). An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. Nature Medicine, 21(12), 1445-1454. https://doi.org/10.1038/nm.3982