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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Cell Adhesion Molecules, Neuronal / metabolism*
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Cell Differentiation
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Cell Movement* / genetics
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Disease Models, Animal
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Enzyme Activation
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Extracellular Matrix Proteins / metabolism*
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Forkhead Transcription Factors / metabolism*
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Gene Expression Regulation, Developmental
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Gene Regulatory Networks
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Green Fluorescent Proteins / metabolism
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Humans
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Magnetic Resonance Imaging
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Malformations of Cortical Development / enzymology
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Malformations of Cortical Development / metabolism*
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Malformations of Cortical Development / pathology*
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Malformations of Cortical Development / surgery
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Mice
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Molecular Sequence Data
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Mosaicism
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Mutation / genetics
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Nerve Tissue Proteins / metabolism*
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Neural Stem Cells / metabolism
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Neurons / metabolism
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Neurons / pathology
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Phenotype
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Small Interfering / metabolism
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Real-Time Polymerase Chain Reaction
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Recombination, Genetic / genetics
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Reelin Protein
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Serine Endopeptidases / metabolism*
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Signal Transduction / genetics
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TOR Serine-Threonine Kinases / metabolism
Substances
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Cell Adhesion Molecules, Neuronal
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Extracellular Matrix Proteins
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FOXG1 protein, human
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Forkhead Transcription Factors
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Nerve Tissue Proteins
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RNA, Small Interfering
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Reelin Protein
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Green Fluorescent Proteins
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MTOR protein, human
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AKT3 protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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RELN protein, human
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Reln protein, mouse
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Serine Endopeptidases