An AKT3-FOXG1-Reelin network underlies defective migration in human focal malformations of cortical development
SCIE
SCOPUS
- Title
- An AKT3-FOXG1-Reelin network underlies defective migration in human focal malformations of cortical development
- Authors
- YUN, EUN JIN; BAEK, SEUNG TAE; Copeland B; Kwon SK; Guemez-Gamboa A; Schaffer AE; Kim S; Kang HC; Song S; Mathern GW; Gleeson JG
- Date Issued
- 2015-12
- Publisher
- NATURE PUBLISHING GROUP
- 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.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/39307
- DOI
- 10.1038/nm.3982
- ISSN
- 1078-8956
- Article Type
- Article
- Citation
- NATURE MEDICINE, vol. 21, no. 12, page. 1445 - +, 2015-12
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