Altered neuronal network and rescue in a human MECP2 duplication model.
Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 functions at the epigenetic level, we tested whether these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders.
Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics, KU Leuven, Leuven, Belgium.
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Nageshappa
Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine, University of California San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, Stem Cell Program, School of Medicine, University of California San Diego, La Jolla, CA, USA.
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Carromeu
Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine, University of California San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, Stem Cell Program, School of Medicine, University of California San Diego, La Jolla, CA, USA.
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Trujillo
Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine, University of California San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, Stem Cell Program, School of Medicine, University of California San Diego, La Jolla, CA, USA.
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Mesci
Institut de Recherches en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.
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Espuny-Camacho
VIB Center for the Biology of Disease, Leuven, Belgium.|KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, KU Leuven, Leuven, Belgium.
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Pasciuto
Institut de Recherches en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.|VIB Center for the Biology of Disease, Leuven, Belgium.|WELBIO, Brussels, Belgium.
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Vanderhaeghen
Department of Development and Regeneration, Cluster Stem Cell Biology and Embryology, Stem Cell Institute Leuven, KU Leuven Medical School, Leuven, Belgium.|VIB Center for the Biology of Disease KU Leuven, Center for Human Genetics, Laboratory of Neuronal Communication, Leuven, Belgium.
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Verfaillie
Department of Development and Regeneration, Cluster Stem Cell Biology and Embryology, Stem Cell Institute Leuven, KU Leuven Medical School, Leuven, Belgium.|VIB Center for the Biology of Disease KU Leuven, Center for Human Genetics, Laboratory of Neuronal Communication, Leuven, Belgium.
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Raitano
Department of Development and Regeneration, Cluster Stem Cell Biology and Embryology, Stem Cell Institute Leuven, KU Leuven Medical School, Leuven, Belgium.|VIB Center for the Biology of Disease KU Leuven, Center for Human Genetics, Laboratory of Neuronal Communication, Leuven, Belgium.|Manipal Institute of Regenerative Medicine, Bangalore, India.
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Kumar
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Centro de Pesquisas René Rachou-FIOCRUZ, Belo Horizonte, MG, Brazil.
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Carvalho
VIB Center for the Biology of Disease, Leuven, Belgium.|KU Leuven Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, KU Leuven, Leuven, Belgium.|Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
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Bagni
Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
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Ramocki
Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine, University of California San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, Stem Cell Program, School of Medicine, University of California San Diego, La Jolla, CA, USA.
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Araujo
Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine, University of California San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, Stem Cell Program, School of Medicine, University of California San Diego, La Jolla, CA, USA.
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Torres
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
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Lupski
Department of Human Genetics, Laboratory for the Genetics of Cognition, Center for Human Genetics, KU Leuven, Leuven, Belgium.|Department of Clinical Genetics, Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
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Van Esch
Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine, University of California San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, Stem Cell Program, School of Medicine, University of California San Diego, La Jolla, CA, USA.
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Muotri
D002454:Cell Differentiation; D003712:Dendrites / Q000378:metabolism; D018628:Gene Dosage / Q000502:physiology; D020440:Gene Duplication / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000502:physiology*; D009415:Nerve Net / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons
D051783:Methyl-CpG-Binding Protein 2