دورية أكاديمية
An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development
| العنوان: | An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development |
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| المساهمون: | College of Medicine, Dept. of Pediatrics, 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, Kang, Hoon Chul, Kim, Sang Woo |
| بيانات النشر: | Nature Publishing Company |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. ; open |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1078-8956 1546-170X |
| العلاقة: | NATURE MEDICINE; J02296; OAK-2015-06178; https://ir.ymlib.yonsei.ac.kr/handle/22282913/156904Test; T201504914; NATURE MEDICINE, Vol.21(12) : 1445-1454, 2015 |
| DOI: | 10.1038/nm.3982 |
| الإتاحة: | https://doi.org/10.1038/nm.3982Test https://ir.ymlib.yonsei.ac.kr/handle/22282913/156904Test |
| حقوق: | CC BY-NC-ND 2.0 KR ; https://creativecommons.org/licenses/by-nc-nd/2.0/krTest/ |
| رقم الانضمام: | edsbas.1DA20212 |
| قاعدة البيانات: | BASE |
| تدمد: | 10788956 1546170X |
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| DOI: | 10.1038/nm.3982 |