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

Ki-Jun Yoon; Ha Nam Nguyen; Gianluca Ursini; Fengyu Zhang; Nam-Shik Kim; Zhexing Wen; Georgia Makri; David Nauen; Joo Heon Shin; Youngbin Park; Raeeun Chung; Eva Pekle; Ce Zhang; Maxwell Towe; Syed Mohammed Qasim Hussaini; Yohan Lee; Dan Rujescu; David St Clair; Joel E Kleinman; Thomas M Hyde; Gregory Krauss; Kimberly M Christian; Judith L Rapoport; Daniel R Weinberger; Hongjun Song; Guo-Li Ming

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

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

Authors

Ki-Jun Yoon¹, Ha Nam Nguyen², Gianluca Ursini³, Fengyu Zhang³, Nam-Shik Kim¹, Zhexing Wen¹, Georgia Makri¹, David Nauen⁴, Joo Heon Shin³, Youngbin Park⁵, Raeeun Chung⁵, Eva Pekle⁵, Ce Zhang¹, Maxwell Towe⁵, Syed Mohammed Qasim Hussaini⁵, Yohan Lee⁶, Dan Rujescu⁷, David St Clair⁸, Joel E Kleinman³, Thomas M Hyde³, Gregory Krauss⁹, Kimberly M Christian¹, Judith L Rapoport⁶, Daniel R Weinberger¹⁰, Hongjun Song¹¹, Guo-Li Ming¹²

Affiliations

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

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actin-Related Protein 2 / metabolism
Adaptor Proteins, Signal Transducing / genetics
Adherens Junctions / genetics*
Adherens Junctions / pathology
Adult
Animals
Autistic Disorder / genetics
Autistic Disorder / metabolism*
Autistic Disorder / pathology
Cell Line
Cell Polarity / genetics
Chromosome Aberrations
Chromosomes, Human, Pair 15 / genetics
DNA Copy Number Variations
Epistasis, Genetic
Genetic Association Studies
Haploinsufficiency
Humans
Induced Pluripotent Stem Cells / physiology*
Intellectual Disability / genetics
Male
Mice
Mice, Inbred Strains
Middle Aged
Neural Stem Cells / physiology*
Risk
Schizophrenia / genetics
Schizophrenia / metabolism*
Schizophrenia / pathology
White People
Wiskott-Aldrich Syndrome Protein Family / metabolism

Substances

Actin-Related Protein 2
Adaptor Proteins, Signal Transducing
CYFIP1 protein, human
WASF1 protein, human
Wiskott-Aldrich Syndrome Protein Family

Supplementary concepts

Duplication 15q11-q13 Syndrome

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding