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

Authors
 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 
Citation
 NATURE MEDICINE, Vol.21(12) : 1445-1454, 2015 
Journal Title
NATURE MEDICINE
ISSN
 1078-8956 
Issue Date
2015
MeSH
Animals ; Base Sequence ; Cell Adhesion Molecules, Neuronal/metabolism* ; Cell Differentiation ; Cell Movement*/genetics ; Disease Models, Animal ; Enzyme Activation ; Extracellular Matrix Proteins/metabolism* ; Forkhead Transcription Factors/metabolism* ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Green Fluorescent Proteins/metabolism ; Humans ; Magnetic Resonance Imaging ; Malformations of Cortical Development/enzymology ; Malformations of Cortical Development/metabolism* ; Malformations of Cortical Development/pathology* ; Malformations of Cortical Development/surgery ; Mice ; Molecular Sequence Data ; Mosaicism ; Mutation/genetics ; Nerve Tissue Proteins/metabolism* ; Neural Stem Cells/metabolism ; Neurons/metabolism ; Neurons/pathology ; Phenotype ; Proto-Oncogene Proteins c-akt/metabolism* ; RNA, Small Interfering/metabolism ; Real-Time Polymerase Chain Reaction ; Recombination, Genetic/genetics ; Serine Endopeptidases/metabolism* ; Signal Transduction/genetics ; TOR Serine-Threonine Kinases/metabolism
Keywords
Postzygotic ; somatic mosaic ; neuropsychiatric ; seizures ; epilepsy ; AKT ; PI3K ; MTOR ; 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.
Files in This Item:
T201504914.pdf Download
DOI
10.1038/nm.3982
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/156904
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