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

Seung Tae Baek, Brett Copeland, Eun Jin Yun, Seok Kyu Kwon, Alicia Guemez-Gamboa, Ashleigh E. Schaffer, Sangwoo Kim, hoonchul kang, Saera Song, Gary W. Mathern, Joseph G. Gleeson

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 AKT3E17K 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.

Original languageEnglish
Pages (from-to)1445-1454
Number of pages10
JournalNature Medicine
Volume21
Issue number12
DOIs
Publication statusPublished - 2015 Dec 1

Fingerprint

Malformations of Cortical Development
Brain
Sirolimus
Phosphatidylinositols
Mutation
Forkhead Transcription Factors
Proto-Oncogene Proteins c-akt
Pediatrics
Transcription
Phosphotransferases
Chemical activation
Partial Epilepsy
Brain Diseases
Defects
Seizures
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Baek, S. T., Copeland, B., Yun, E. J., Kwon, S. K., Guemez-Gamboa, A., Schaffer, A. E., ... Gleeson, J. G. (2015). An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. Nature Medicine, 21(12), 1445-1454. https://doi.org/10.1038/nm.3982
Baek, Seung Tae ; Copeland, Brett ; Yun, Eun Jin ; Kwon, Seok Kyu ; Guemez-Gamboa, Alicia ; Schaffer, Ashleigh E. ; Kim, Sangwoo ; kang, hoonchul ; Song, Saera ; Mathern, Gary W. ; Gleeson, Joseph G. / An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. In: Nature Medicine. 2015 ; Vol. 21, No. 12. pp. 1445-1454.
@article{d0d165b6ca3242ea96abcfd117c1ee11,
title = "An AKT3-FOXG1-reelin network underlies defective migration in human focal 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 AKT3E17K 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.",
author = "Baek, {Seung Tae} and Brett Copeland and Yun, {Eun Jin} and Kwon, {Seok Kyu} and Alicia Guemez-Gamboa and Schaffer, {Ashleigh E.} and Sangwoo Kim and hoonchul kang and Saera Song and Mathern, {Gary W.} and Gleeson, {Joseph G.}",
year = "2015",
month = "12",
day = "1",
doi = "10.1038/nm.3982",
language = "English",
volume = "21",
pages = "1445--1454",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "12",

}

Baek, ST, Copeland, B, Yun, EJ, Kwon, SK, Guemez-Gamboa, A, Schaffer, AE, Kim, S, kang, H, Song, S, Mathern, GW & Gleeson, JG 2015, 'An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development', Nature Medicine, vol. 21, no. 12, pp. 1445-1454. https://doi.org/10.1038/nm.3982

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, hoonchul; Song, Saera; Mathern, Gary W.; Gleeson, Joseph G.

In: Nature Medicine, Vol. 21, No. 12, 01.12.2015, p. 1445-1454.

Research output: Contribution to journalArticle

TY - JOUR

T1 - An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development

AU - Baek, Seung Tae

AU - Copeland, Brett

AU - Yun, Eun Jin

AU - Kwon, Seok Kyu

AU - Guemez-Gamboa, Alicia

AU - Schaffer, Ashleigh E.

AU - Kim, Sangwoo

AU - kang, hoonchul

AU - Song, Saera

AU - Mathern, Gary W.

AU - Gleeson, Joseph G.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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 AKT3E17K 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.

AB - 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 AKT3E17K 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.

UR - http://www.scopus.com/inward/record.url?scp=84949564339&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949564339&partnerID=8YFLogxK

U2 - 10.1038/nm.3982

DO - 10.1038/nm.3982

M3 - Article

VL - 21

SP - 1445

EP - 1454

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 12

ER -

Baek ST, Copeland B, Yun EJ, Kwon SK, Guemez-Gamboa A, Schaffer AE et al. An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. Nature Medicine. 2015 Dec 1;21(12):1445-1454. https://doi.org/10.1038/nm.3982