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 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.
authors.affiliation: Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA.|Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA.
authors.forename: Seung Tae
authors.identifier: http://orcid.org/0000-0003-0040-1501
authors.initials: ST
authors.lastname: Baek
authors.affiliation: Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Copeland
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Yun
authors.affiliation: Department of Neuroscience, Columbia University, New York, New York, USA.
authors.forename: Seok-Kyu
authors.initials: SK
authors.lastname: Kwon
authors.affiliation: Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Guemez-Gamboa
authors.affiliation: Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA.
authors.forename: Ashleigh E
authors.initials: AE
authors.lastname: Schaffer
authors.affiliation: Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Kim
authors.affiliation: Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA.|Department of Pediatrics, Division of Pediatric Neurology, Pediatric Epilepsy Clinics, Severance Children's Hospital, Seoul, South Korea.|Epilepsy Research Center, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Hoon-Chul
authors.initials: HC
authors.lastname: Kang
authors.affiliation: Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA.
authors.forename: Saera
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Neurosurgery, Mattel Children's Hospital, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.|Department of Psychiatry and Biobehavioral Sciences, Mattel Children's Hospital, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Mathern
authors.affiliation: Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA.|Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA.|Neurogenetics Laboratory, Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000818:Animals; D001483:Base Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D054220:Malformations of Cortical Development / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D051379:Mice; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011995:Recombination, Genetic / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D000091042:Reelin Protein; D049452:Green Fluorescent Proteins; C546842:MTOR protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases