title: Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity.
abstract: Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ki-Jun
authors.initials: KJ
authors.lastname: Yoon
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ha Nam
authors.initials: HN
authors.lastname: Nguyen
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ursini
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Fengyu
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Nam-Shik
authors.initials: NS
authors.lastname: Kim
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Zhexing
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Makri
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: David
authors.initials: D
authors.lastname: Nauen
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Joo Heon
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Youngbin
authors.initials: Y
authors.lastname: Park
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Raeeun
authors.initials: R
authors.lastname: Chung
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Pekle
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ce
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Towe
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Syed Mohammed Qasim
authors.initials: SM
authors.lastname: Hussaini
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, Ludwig-Maximilians University, Nussbaumstrasse 7, 80336, Munich, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.affiliation: University of Aberdeen Royal Cornhill Hospital, Aberdeen AB25 2ZD, UK.
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Krauss
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Christian
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA.
authors.forename: Judith L
authors.initials: JL
authors.lastname: Rapoport
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: shongju1@jhmi.edu.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: gming1@jhmi.edu.
authors.forename: Guo-Li
authors.initials: GL
authors.lastname: Ming
mesh_terms: D051377:Actin-Related Protein 2 / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D022005:Adherens Junctions / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D016764:Cell Polarity / Q000235:genetics; D002869:Chromosome Aberrations; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D056915:DNA Copy Number Variations; D004843:Epistasis, Genetic; D056726:Genetic Association Studies; D057895:Haploinsufficiency; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D058953:Neural Stem Cells / Q000502:physiology*; D012306:Risk; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044465:White People; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism
chemical_list: D051377:Actin-Related Protein 2; D048868:Adaptor Proteins, Signal Transducing; C109916:CYFIP1 protein, human; C114864:WASF1 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family