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Left: Human neural stem cells form rosettes as they grow into different cell types, with ringlike patterns of PKCλ protein in the center. Right: A neural rosette with a 15q11.2 microdeletion, a risk factor for schizophrenia, appears disorganized and lacks the ringlike PKCλ protein structure, suggesting this risk factor acts early in neurodevelopment.

Schizophrenia gene affects brain cell development

While no single genetic mutation is known to cause schizophrenia, genomewide association studies have identified gene variations in the developing brains of mice that are more common in humans with schizophrenia than in the general population.

One of these is a missing area of the gene labeled 15q11.2. "While this deletion is linked to schizophrenia, having extra copies of this part of the genome also raises the risk of autism," notes Guo-li Ming, MD, PhD, a professor of neurology and neuroscience in the Johns Hopkins University School of Medicine's Institute for Cell Engineering.

Johns Hopkins researchers found that loss of part of the 15q11.2 gene alters the developing skeleton of brain cells, which in turn disrupts the orderly layers these cells normally form in the creation of the brain.

"This is an important step toward understanding what physically happens in the developing brain that puts people at risk for schizophrenia."

Guo-li Ming, MD, PhD, professor, neurology and neuroscience, Johns Hopkins University School of Medicine, Institute for Cell Engineering

For her study, Ming's research group — along with that of her husband and collaborator, Hongjun Song, PhD professor of neurology and neuroscience — used skin cells from people with schizophrenia who were missing part of 15q11.2 on one of their chromosomes. (Because everyone carries two copies of their genome, the patients each had an intact copy of 15q11.2 as well.) Researchers grew the human skin cells in a dish and coaxed them to first become induced pluripotent stem cells, and secondly to form neural progenitor cells, a stem cell found in the developing brain.

"Normally, neural progenitor cells will form orderly rings when grown in a dish, but those with the 15q11.2 deletion did not," Ming says. To find out which of the four known genes in the missing piece of 15q11.2 was responsible for this loss of structural order, the scientists engineered groups of progenitor cells from each of the suspect genes to produce less protein than normal. The crucial ingredient for ring formation turned out to be the gene called CYFIP1.

They then altered the genes of neural progenitor cells in mouse embryos to make less of the protein created by CYFIP1. These fetal mice turned out to have similar defects in neural brain structure as those in petri dish-grown human cells. CYFIP1, therefore, plays a role in building the skeleton which gives shape to each cell — and its loss affects adheren junctions where the skeletons of two neighboring cells connect.

Having less CYFIP1 protein also caused some neurons
to end up in the wrong layer of the developing brain.

"During development, new neurons reach their final destination by 'climbing' the tendrils of neural progenitor cells," Ming says. "We think that disrupted adherens junctions don't provide a stable "rope" for new neurons to climb to get to their desired location."

Researchers also found that CYFIP1 is part of a protein complex called WAVE, which is key in building the cell skeleton. Many people with a CYFIP1 deletion do not get schizophrenia, so the team suspected there must be another defect in the WAVE complex that contributes to schizophrenia.

Analyzing data from genomewide association studies, they found an additional variation in the gene ACTR2/Arp2 also in the WAVE complex. Combined with the CYFIP1 deletion, ACTR2/Arp2 increased the risk of schizophrenia more than either of these genetic variations alone.

The study provides a method for how other mental illnesses might be similarly investigated. "Using induced pluripotent stem cells from people with schizophrenia allowed us to see how their genes affected brain development," says Song. "We'd like to continue investigating other defects of the adult brain."

The report appears in the July issue of Cell Stem Cell.

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.

Other authors on the paper are Ki-Jun Yoon, Ha Nam Nguyen, Namshik Kim, Zhexing Wen, Georgia Makri, David Nauen, Joo Heon Shin, Youngbin Park, Raeeun Chung, Eva Pekle, Ce Zhang, Maxwell Towe, Syed Mohammed Qasim Hussaini, Gregory Krauss and Kimberly M. Christian of the Johns Hopkins University School of Medicine; Gianluca Ursini, Fengyu Zhang, Joel E. Kleinman, Thomas M. Hyde, Daniel R. Weinberger of the Lieber Institute for Brain Development at The Johns Hopkins University; Judith L. Rapoport and Yohan Lee of the National Institute of Mental Health; Dan Rujescu of the Ludwig Maximilian University; and David St. Clair of the University of Aberdeen.

The study was funded by the National Institute of Neurological Disorders and Stroke (grant numbers NS048271 and NS047344), the National Institute of Child Health and Human Development (grant number HD069184), the National Institute of Mental Health (grant numbers MH087874 and F31MH102978), the Brain & Behavior Research Foundation (NARSAD), the Maryland Stem Cell Research Fund, the Simons Foundation Autism Research Initiative, the International Mental Health Research Organization and the Lieber Institute for Brain Development.

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Genetic Risk and Stressful Early Infancy Join to Increase Risk for Schizophrenia
http://m.hopkinsmedicine.org/news/media/releases/genetic_risk_and_
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http://www.hopkinsmedicine.org/news/media/releases/hopkins_researchers_
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http://www.hopkinsmedicine.org/news/media/releases/johns_hopkins_team_
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Normal Role for Schizophrenia Risk Gene Identified
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