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


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.

SUBMITTER: Baek ST 

PROVIDER: S-EPMC4955611 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Baek Seung Tae ST   Copeland Brett B   Yun Eun-Jin EJ   Kwon Seok-Kyu SK   Guemez-Gamboa Alicia A   Schaffer Ashleigh E AE   Kim Sangwoo S   Kang Hoon-Chul HC   Song Saera S   Mathern Gary W GW   Gleeson Joseph G JG  

Nature medicine 20151102 12


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 foun  ...[more]

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