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

Nature Medicine volume 21, pages 1445–1454 (2015)Cite this article

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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.

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Figure 1: Modeling FMCD mutation in developing brain.
Figure 2: Cellular pathology from AKT3 activation in human neural progenitor cells.
Figure 3: AKT3 kinase activity is essential for aberrant migration phenotype.
Figure 4: Pharmacological rescue of AKT3E17K-induced phenotypes.
Figure 5: Genetic recombination of AKT3E17K defines reversibility of FMCD networks.
Figure 6: Neuronal migration defects rescued by Reln siRNA.

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Acknowledgements

We thank N. Cai, M. Huynh, T. Chirwa, K. Um, J. Silhavy and U. Yang for technical expertise. This work was supported by the US National Institutes of Health (grant no. R01NS083823; J.G.G. and G.W.M.), the Simons Foundation for Autism Research (grant no. 275275; J.G.G.), the Howard Hughes Medical Institute (J.G.G.), the 2014 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Grant from the Brain & Behavior Research Foundation (grant no. 22892; S.T.B.), a Human Frontier Science Program Long-Term Fellowship (S.-K.K.), an A.P. Giannini Foundation Fellowship (A.E.S.) and an NIH NICHD K99/R00 Pathway to Independence Award (grant no. K99HD082337; A.E.S.). G.W.M. was supported by the Dr. Alfonsina Q. Davies Endowed Chair in honor of Paul Crandall MD for Epilepsy Research. We thank the UCSD Neuroscience Microscopy Core P30 NS047101 for imaging support, K. Jepsen from the UCSD Institute for Genomic Medicine Core Facility, the UCSD Human Embryonic Stem Cell Core Facility, A. Roberts from the Scripps Research Institute Animal Core Facility, I. Verma (Salk Institute) for the pBOB-Switch vector, A. Acharya (University of Texas Southwestern Medical Center) for the Cre-expressing adenovirus, G. Fishell (New York University) for the Foxg1 plasmid, and P. Mischel, I. Martin-Valencia, T. Curran and T. Park for discussions.

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Authors and Affiliations

  1. Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, USA

    Seung Tae Baek, Brett Copeland, Alicia Guemez-Gamboa, Hoon-Chul Kang, Saera Song & Joseph G Gleeson

  2. Department of Neurosciences, University of California San Diego (UCSD), La Jolla, California, USA

    Seung Tae Baek, Ashleigh E Schaffer & Joseph G Gleeson

  3. Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Eun-Jin Yun

  4. Department of Neuroscience, Columbia University, New York, New York, USA

    Seok-Kyu Kwon

  5. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea

    Sangwoo Kim

  6. Department of Pediatrics, Division of Pediatric Neurology, Pediatric Epilepsy Clinics, Severance Children's Hospital, Seoul, South Korea

    Hoon-Chul Kang

  7. Epilepsy Research Center, Yonsei University College of Medicine, Seoul, South Korea

    Hoon-Chul Kang

  8. Department of Neurosurgery, Mattel Children's Hospital, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA

    Gary W Mathern

  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

    Gary W Mathern

  10. Neurogenetics Laboratory, Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Joseph G Gleeson

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Contributions

S.T.B. and J.G.G. designed experiments, analyzed data and wrote the manuscript. B.C. performed bioinformatics analysis of RNA-seq results. S.T.B. performed experiments. E.-J.Y. performed FOXG1 chromatin immunoprecipitation. S.-K.K. helped with in utero electroporation. A.G.-G., A.E.S., S.K., H.-C.K., S.S. and G.W.M. contributed key reagents and advice. J.G.G. conceived and supervised the project.

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Correspondence to Joseph G Gleeson.

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Baek, S., Copeland, B., Yun, EJ. et al. An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. Nat Med 21, 1445–1454 (2015). https://doi.org/10.1038/nm.3982

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