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An AKT3-FOXG1-Reelin Network Underlies Defective Migration in Human Focal Malformations of Cortical Development
Focal malformations of cortical development (FMCD) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the PI3K-AKT-mTOR pathway are found in a wide range of brain diseases, including FMCD. It remains unclear how a mutation in a small fraction of c...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955611/ https://www.ncbi.nlm.nih.gov/pubmed/26523971 http://dx.doi.org/10.1038/nm.3982 |
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author | Baek, Seung Tae Copeland, Brett Yun, Eun-Jin Kwon, Seok-Kyu Guemez-Gamboa, Alicia Schaffer, Ashleigh E. Kim, Sangwoo Kang, Hoon-Chul Song, Saera Mathern, Gary W. Gleeson, Joseph G. |
author_facet | Baek, Seung Tae Copeland, Brett Yun, Eun-Jin Kwon, Seok-Kyu Guemez-Gamboa, Alicia Schaffer, Ashleigh E. Kim, Sangwoo Kang, Hoon-Chul Song, Saera Mathern, Gary W. Gleeson, Joseph G. |
author_sort | Baek, Seung Tae |
collection | PubMed |
description | Focal malformations of cortical development (FMCD) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the PI3K-AKT-mTOR pathway are found in a wide range of brain diseases, including FMCD. It remains unclear how a mutation in a small fraction of cells can disrupt the architecture of the entire hemisphere. We show that, within human FMCD brain, cells showing activation of this pathway were enriched for the mutation. Introducing the FMCD mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed reelin misexpression, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to FOXG1-mediated de-repression of reelin transcription. Treatments aimed at 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. |
format | Online Article Text |
id | pubmed-4955611 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-49556112016-07-21 An AKT3-FOXG1-Reelin Network Underlies Defective Migration in Human Focal Malformations of Cortical Development Baek, Seung Tae Copeland, Brett Yun, Eun-Jin Kwon, Seok-Kyu Guemez-Gamboa, Alicia Schaffer, Ashleigh E. Kim, Sangwoo Kang, Hoon-Chul Song, Saera Mathern, Gary W. Gleeson, Joseph G. Nat Med Article Focal malformations of cortical development (FMCD) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the PI3K-AKT-mTOR pathway are found in a wide range of brain diseases, including FMCD. It remains unclear how a mutation in a small fraction of cells can disrupt the architecture of the entire hemisphere. We show that, within human FMCD brain, cells showing activation of this pathway were enriched for the mutation. Introducing the FMCD mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed reelin misexpression, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to FOXG1-mediated de-repression of reelin transcription. Treatments aimed at 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. 2015-11-02 2015-12 /pmc/articles/PMC4955611/ /pubmed/26523971 http://dx.doi.org/10.1038/nm.3982 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Baek, Seung Tae Copeland, Brett Yun, Eun-Jin Kwon, Seok-Kyu Guemez-Gamboa, Alicia Schaffer, Ashleigh E. Kim, Sangwoo Kang, Hoon-Chul Song, Saera Mathern, Gary W. Gleeson, Joseph G. An AKT3-FOXG1-Reelin Network Underlies Defective Migration in Human Focal Malformations of Cortical Development |
title | An AKT3-FOXG1-Reelin Network Underlies Defective Migration in Human Focal Malformations of Cortical Development |
title_full | An AKT3-FOXG1-Reelin Network Underlies Defective Migration in Human Focal Malformations of Cortical Development |
title_fullStr | An AKT3-FOXG1-Reelin Network Underlies Defective Migration in Human Focal Malformations of Cortical Development |
title_full_unstemmed | An AKT3-FOXG1-Reelin Network Underlies Defective Migration in Human Focal Malformations of Cortical Development |
title_short | An AKT3-FOXG1-Reelin Network Underlies Defective Migration in Human Focal Malformations of Cortical Development |
title_sort | akt3-foxg1-reelin network underlies defective migration in human focal malformations of cortical development |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955611/ https://www.ncbi.nlm.nih.gov/pubmed/26523971 http://dx.doi.org/10.1038/nm.3982 |
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