Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity

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

doi:10.1016/j.stem.2015.02.003

Cited by 34 publications

(71 citation statements)

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“…These extracellular matrix proteins include gene families such as neural cell adhesion molecules, neuroligins and neurexins that are critical for cellular differentiation and migration 29 , and are postulated as a possible mechanism for the etiopathogenesis of schizophrenia 30 . Previous studies have demonstrated that schizophrenia NPCs have abnormal expression for extracellular matrix and cell adhesion genes 10,31 , accompanied by deficits in migration 10 .…”

Section: Discussionmentioning

confidence: 99%

Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons

et al. 2016

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IMPORTANCE Schizophrenia candidate genes participate in common molecular pathways that are regulated by activity-dependent changes in neurons. One important next step is to further our understanding on the role of activity-dependent changes of genes expression in the etiopathogenesis of schizophrenia. OBJECTIVE To examine whether neuronal activity-dependent changes of gene expression is dysregulated in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Neurons differentiated from human induced pluripotent stem cells (hiPSCs) derived from 4 cases with schizophrenia and 4 unaffected controls were depolarized using potassium chloride. RNA was extracted followed by genome-wide profiling of the transcriptome. MAIN OUTCOMES AND MEASURES We performed differential expression analysis and gene co-expression analysis to identify activity-dependent or disease-specific changes of the transcriptome. Gene expression differences were assessed with linear models. Further, we used gene set analyses to identify co-expressed modules that are enriched for schizophrenia risk genes. RESULTS We identified 1,669 genes that are significantly different in schizophrenia-associated vs. control hiPSC-derived neurons and 1,199 genes that are altered in these cells in response to depolarization (linear models at false discovery rate ≤ 0.05). We show that the effect of activity-dependent changes of gene expression in schizophrenia-associated neurons (59 significant genes at false discovery rate ≤ 0.05) is attenuated compared to controls (594 significant genes at false discovery rate ≤ 0.05). Using gene co-expression analysis, we identified 2 modules (turquoise and brown) that are associated with diagnosis status and 2 modules (yellow and green) that are associated with depolarization at false discovery rate ≤ 0.05. For 3 out of the 4 modules we found enrichment with schizophrenia-associated variants: brown (Fisher’s P = 0.002), turquoise (Fisher’s P = 0.044) and yellow (Fisher’s P = 0.018). CONCLUSIONS AND RELEVANCE Our results show that schizophrenia candidate genes cluster within gene networks that are associated with a blunted effect of activity-dependent changes of gene expression in schizophrenia-associated neurons. Overall, these findings link schizophrenia candidate genes with specific molecular functions in neurons, which could be utilized to examine underlying mechanisms and therapeutic interventions related to schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons

et al. 2016

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“…Among the four genes in the deleted region, CYFIP1 haploinsufficiency was identified as responsible for the phenotype, although dysregulation of the cytoskeletal modulating WAVE complex. By comparison, NPCs from two SCZ patients with DISC1 point mutations did not show these deficits , supporting the idea that SCZ can arise through multiple developmental and cellular pathways and/or is heterogeneous in nature.…”

Section: Latest Findings In Cell‐based Analysis Of Neuropsychiatric Dmentioning

confidence: 61%

Concise Review: Progress and Challenges in Using Human Stem Cells for Biological and Therapeutics Discovery: Neuropsychiatric Disorders

Panchision

2016

Stem Cells

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In facing the daunting challenge of using human embryonic and induced pluripotent stem cells (hESCs, hiPSCs) to study complex neural circuit disorders such as schizophrenia (SCZ), mood and anxiety disorders and autism spectrum disorders (ASDs), a 2012 National Institute of Mental Health workshop produced a set of recommendations to advance basic research and engage industry in cell-based studies of neuropsychiatric disorders. This review describes progress in meeting these recommendations, including the development of novel tools, strides in recapitulating relevant cell and tissue types, insights into the genetic basis of these disorders that permit integration of risk-associated gene regulatory networks with cell/circuit phenotypes, and promising findings of patient-control differences using cell-based assays. However, numerous challenges are still being addressed, requiring further technological development, approaches to resolve disease heterogeneity and collaborative structures for investigators of different disciplines. Additionally, since data obtained so far is on small sample sizes, replication in larger sample sets is needed. A number of individual success stories point to a path forward in developing assays to translate discovery science to therapeutics development.

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“…iPSC lines were derived from two patients carrying the same frameshift mutation in the DISC1 gene and three unaffected individuals. Yoon and colleagues demonstrated that iPSCs derived from 15q11.2 deletion carriers had significant defects in neural rosette formation (100). They also established the causality between DISC1 mutations and the changes observed by repeating some of the analysis in several isogenic cell lines.…”

Section: Current Status Of Ipscs-based Research For Psychiatric Disormentioning

confidence: 98%

“…Indeed, monolayer based forebrain glutamatergic neuron differentiation has been the platform of choice for the majority of disease modeling articles published so far (10, 11, 15, 30,38,53,74,77,81,94,100). Indeed, monolayer based forebrain glutamatergic neuron differentiation has been the platform of choice for the majority of disease modeling articles published so far (10, 11, 15, 30,38,53,74,77,81,94,100).…”

Section: Generation Of Disease Relevant Neuronal Cell Types From Humamentioning

confidence: 99%

Understanding neurodevelopmental disorders using human pluripotent stem cell‐derived neurons

Tamburini

2017

Brain Pathology

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Research into psychiatric disorders has long been hindered by the lack of appropriate models. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient-specific cells, which in principle can be differentiated into all disease-relevant somatic cell types to create in vitro models of the disorder of interest. Here, neuronal differentiation protocols available for this purpose and the current progress on iPSCs-based models of schizophrenia, autism spectrum disorders and bipolar disorder were reviewed. We also discuss the impact of the recently developed CRISPR/Cas9 genome editing tool in the disease modeling field. Genetically engineered mutation of disease risk alleles in well characterized reference "control" hPSCs or correction of disease risk variants in patient iPSCs has been used as a powerful means to establish causality of the identified cellular pathology. Together, iPSC reprogramming and CRISPR/CAS9 genome editing technology have already significantly contributed to our understanding of the developmental origin of some major psychiatric disorders. The challenge ahead is the identification of shared mechanisms in their etiology, which will ultimately be relevant to the development of new treatments.

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Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity

Cited by 34 publications

References 0 publications

Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons

Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons

Concise Review: Progress and Challenges in Using Human Stem Cells for Biological and Therapeutics Discovery: Neuropsychiatric Disorders

Understanding neurodevelopmental disorders using human pluripotent stem cell‐derived neurons

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