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Cell Stem Cell. 2014 Jul 3;15(1):79-91. doi: 10.1016/j.stem.2014.05.003.

Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity.

Author information

  • 1Institute 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.
  • 2Institute 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.
  • 3Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 4Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 6Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA.
  • 7Department of Psychiatry, Ludwig-Maximilians University, Nussbaumstrasse 7, 80336, Munich, Germany.
  • 8University of Aberdeen Royal Cornhill Hospital, Aberdeen AB25 2ZD, UK.
  • 9Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 10Department 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.
  • 11Institute 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.
  • 12Institute 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.

Erratum in

  • Cell Stem Cell. 2015 Mar 5;16(3):339.

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24996170
[PubMed - indexed for MEDLINE]
PMCID:
PMC4237009
Free PMC Article

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