title: A quantitative framework to evaluate modeling of cortical development by neural stem cells.
abstract: Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease.
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: de la Torre-Ubieta
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Neelroop N
authors.initials: NN
authors.lastname: Parikshak
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Israel A
authors.initials: IA
authors.lastname: Hernández
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Marchetto
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Dylan K
authors.initials: DK
authors.lastname: Baker
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Daning
authors.initials: D
authors.lastname: Lu
authors.affiliation: Center for Stem Cell Biology and Engineering, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Cassidy R
authors.initials: CR
authors.lastname: Hinman
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lowe
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Wexler
authors.affiliation: School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
authors.affiliation: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.affiliation: Molecular, Cellular and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kosik
authors.affiliation: Neurogenetics Program, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dhg@mednet.ucla.edu.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D001185:Artificial Intelligence / Q000639:trends; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology*; D053595:Embryonic Stem Cells / Q000502:physiology*; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D008297:Male; D008959:Models, Neurological; D058953:Neural Stem Cells / Q000502:physiology*