title: Altered proliferation and networks in neural cells derived from idiopathic autistic individuals.
abstract: Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a β-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.
authors.affiliation: The Salk Institute, Laboratory of Genetics, La Jolla, CA 92037, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Marchetto
authors.affiliation: University of California San Francisco, Department of Pediatrics, Institute for Human Genetics, CA 94143, USA.
authors.forename: Haim
authors.initials: H
authors.lastname: Belinson
authors.affiliation: University of California Los Angeles, Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, Los Angeles, CA 90402, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: University of California San Diego, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, La Jolla, CA 92093-0695, USA.
authors.forename: Beatriz C
authors.initials: BC
authors.lastname: Freitas
authors.affiliation: Case Western Reserve University, Department of Genetics and Genome Sciences, Cleveland, OH 44106, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Fu
authors.affiliation: The Salk Institute, Laboratory of Genetics, La Jolla, CA 92037, USA.
authors.forename: Krishna
authors.initials: K
authors.lastname: Vadodaria
authors.affiliation: University of California San Diego, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, La Jolla, CA 92093-0695, USA.|University of São Paulo, Department of Obstetrics, Department of Surgery, Center for Cellular and Molecular Therapy, São Paulo, Brazil.
authors.forename: Patricia
authors.initials: P
authors.lastname: Beltrao-Braga
authors.affiliation: University of California San Diego, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, La Jolla, CA 92093-0695, USA.
authors.forename: Cleber A
authors.initials: CA
authors.lastname: Trujillo
authors.affiliation: The Salk Institute, Laboratory of Genetics, La Jolla, CA 92037, USA.
authors.forename: Ana P D
authors.initials: APD
authors.lastname: Mendes
authors.affiliation: University of Rochester School of Medicine and Dentistry, Department of Neuroscience, 601 Elmwood Avenue, Box 603 Rochester, NY 14642.
authors.forename: Krishnan
authors.initials: K
authors.lastname: Padmanabhan
authors.affiliation: The Salk Institute, Laboratory of Genetics, La Jolla, CA 92037, USA.|University of California San Diego, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, La Jolla, CA 92093-0695, USA.
authors.forename: Yanelli
authors.initials: Y
authors.lastname: Nunez
authors.affiliation: University of California Los Angeles, Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, Los Angeles, CA 90402, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ou
authors.affiliation: The Salk Institute, Laboratory of Genetics, La Jolla, CA 92037, USA.
authors.forename: Himanish
authors.initials: H
authors.lastname: Ghosh
authors.affiliation: The Salk Institute, Laboratory of Genetics, La Jolla, CA 92037, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wright
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Brennand
authors.affiliation: University of California San Diego, Department of Neurosciences, La Jolla, CA 92093, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Pierce
authors.affiliation: University of California San Diego, Department of Neurosciences, La Jolla, CA 92093, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Eichenfield
authors.affiliation: University of California San Diego, Department of Neurosciences, La Jolla, CA 92093, USA.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Pramparo
authors.affiliation: University of California San Diego, Department of Neurosciences, La Jolla, CA 92093, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Eyler
authors.affiliation: University of California San Diego, Department of Neurosciences, La Jolla, CA 92093, USA.
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Barnes
authors.affiliation: University of California San Diego, Department of Neurosciences, La Jolla, CA 92093, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Courchesne
authors.affiliation: University of California Los Angeles, Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, Los Angeles, CA 90402, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: The Salk Institute, Laboratory of Genetics, La Jolla, CA 92037, USA.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.affiliation: University of California San Francisco, Department of Pediatrics, Institute for Human Genetics, CA 94143, USA.|Case Western Reserve University, Department of Genetics and Genome Sciences, Cleveland, OH 44106, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.affiliation: University of California San Diego, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, La Jolla, CA 92093-0695, USA.
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
mesh_terms: D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000378:metabolism / Q000503:physiopathology; D001321:Autistic Disorder / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D046509:Tissue Culture Techniques / Q000379:methods*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051176:beta Catenin; D007334:Insulin-Like Growth Factor I