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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
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.
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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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