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Nat Med. 2015 Dec;21(12):1445-54. doi: 10.1038/nm.3982. Epub 2015 Nov 2.

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

Author information

1
Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA.
2
Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA.
3
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
4
Department of Neuroscience, Columbia University, New York, New York, USA.
5
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
6
Department of Pediatrics, Division of Pediatric Neurology, Pediatric Epilepsy Clinics, Severance Children's Hospital, Seoul, South Korea.
7
Epilepsy Research Center, Yonsei University College of Medicine, Seoul, South Korea.
8
Department of Neurosurgery, Mattel Children's Hospital, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
9
Department of Psychiatry and Biobehavioral Sciences, Mattel Children's Hospital, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
10
Neurogenetics Laboratory, Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

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.

PMID:
26523971
PMCID:
PMC4955611
DOI:
10.1038/nm.3982
[Indexed for MEDLINE]
Free PMC Article

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