Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity
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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.
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Stem cell-based models are beginning to be used for characterizing cellular defects linked to pathological gene variation.
“and stem cell-based models are beginning to be used for characterizing cellular defects linked to pathological gene variation 58-60 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [58]
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- Authors
- Yoon, K.-J., Nguyen, H. N., Ursini, G., Zhang, F., Kim, N.-S., Wen, Z., Makri, G., Nauen, D., Shin, J. H., Park, Y., Chung, R., Pekle, E., Zhang, C., Towe, M., Hussaini, S. M. Q., Lee, Y., Rujescu, D., St. Clair, D., Kleinman, J. E., Hyde, T. M., Krauss, G., Christian, K. M., Rapoport, J. L., Weinberger, D. R., Song, H., & Ming, G.-L.
- Affiliations
- Johns Hopkins University (US)
- National Institute of Mental Health (US)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Song, Hongjun
- Ming, Guo-li
- ORCID
- Yoon, Ki-Jun
- Nguyen, Ha Nam
- Ursini, Gianluca
- Zhang, Fengyu
- Kim, Nam-Shik
- Wen, Zhexing
- Makri, Georgia
- Nauen, David
- Shin, Joo Heon
- Park, Youngbin
- Zhang, Ce
- Towe, Maxwell
- Hussaini, Syed Mohammed Qasim
- Lee, Yohan
- Rujescu, Dan
- Kleinman, Joel E.
- Hyde, Thomas M.
- Krauss, Gregory
- Christian, Kimberly M.
- Weinberger, Daniel R.
- Song, Hongjun
- Ming, Guo-li
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 15
- Issue
- 1
- Pages
- 79-91
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4237009
- OpenAlex
- W2136929119
- Cited by
- 240
- References
- 53
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 7 · 2023: 13 · 2022: 16 · 2021: 16 · 2020: 34 · 2019: 21 · 2018: 29 · 2017: 38 · 2016: 30 · 2015: 24 · 2014: 7
- FWCI
- 21.67
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-03-05)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R21MH087874, R33MH087874, MH087874, F31MH102978)
- National Institute of General Medical Sciences (T32GM008752)
- National Institute of Neurological Disorders and Stroke (NS 048271, R01NS047344, NS 047344, R01NS048271, R37NS047344, R56NS047344)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD069184, HD069184)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- schizophrenia, CYFIP1, WAVE complex, adherens junctions, apical polarity, neural progenitor cells, radial glia, cortical development, haploinsufficiency, epistasis, iPSC-derived neurons, neuropsychiatric disorders
- MeSH terms
- Adult, Animals, Autistic Disorder, Cell Line, Chromosome Aberrations, Chromosomes, Human, Pair 15, Epistasis, Genetic, Humans, Male, Intellectual Disability, Mice, Inbred Strains, Middle Aged, Risk, Schizophrenia, Cell Polarity, Adherens Junctions, White People, Adaptor Proteins, Signal Transducing, Wiskott-Aldrich Syndrome Protein Family, Actin-Related Protein 2, Mice, Genetic Association Studies, DNA Copy Number Variations, Induced Pluripotent Stem Cells, Haploinsufficiency, Neural Stem Cells
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