Cell Stem Cell
Volume 15, Issue 1, 3 July 2014, Pages 79-91
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Article
Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity

https://doi.org/10.1016/j.stem.2014.05.003Get rights and content
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Highlights

  • hiPSC-derived neural rosettes carrying 15q11.2 CNV exhibit polarity defects

  • CYFIP1 haploinsufficiency causes polarity defects via WAVE complex destabilization

  • CYFIP1 and WAVE signaling regulate radial glia cells in the developing mouse cortex

  • CYFIP1 and ACTR2 interact epistatically to affect risk for schizophrenia

Summary

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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