Focal Adhesion Dynamics Are Altered in Schizophrenia

Fan, Ying; Abrahamsen, Greger; Mills, Richard J.; Calderón, C; Tee, Jing Yang; Leyton, Lisette; Murrell, Wayne; Cooper-White, Justin J.; McGrath, John J.; Mackay‐Sim, Alan

doi:10.1016/j.biopsych.2013.01.020

Cited by 70 publications

(66 citation statements)

References 64 publications

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“…Both CRK and RAPGEF1 genes are included in the SZGR2.0 database (Jia et al, 2017) as related to SCZ risk. Remarkably, dynamics of focal adhesion is altered in neural stem/progenitor cell cultures derived from olfactory neuroepithelium of SCZ patients (Féron et al, 1999; Fan et al, 2013), a cellular model similar to CNON cells. Focal adhesion controls motility (Mitra et al, 2005) is also affected in neural stem/progenitor cells derived from SCZ patients (Tee et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Igolkina

Armoskus

Newman

et al. 2018

Front. Mol. Neurosci.

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Schizophrenia (SCZ) is a psychiatric disorder of unknown etiology. There is evidence suggesting that aberrations in neurodevelopment are a significant attribute of schizophrenia pathogenesis and progression. To identify biologically relevant molecular abnormalities affecting neurodevelopment in SCZ we used cultured neural progenitor cells derived from olfactory neuroepithelium (CNON cells). Here, we tested the hypothesis that variance in gene expression differs between individuals from SCZ and control groups. In CNON cells, variance in gene expression was significantly higher in SCZ samples in comparison with control samples. Variance in gene expression was enriched in five molecular pathways: serine biosynthesis, PI3K-Akt, MAPK, neurotrophin and focal adhesion. More than 14% of variance in disease status was explained within the logistic regression model (C-value = 0.70) by predictors accounting for gene expression in 69 genes from these five pathways. Structural equation modeling (SEM) was applied to explore how the structure of these five pathways was altered between SCZ patients and controls. Four out of five pathways showed differences in the estimated relationships among genes: between KRAS and NF1, and KRAS and SOS1 in the MAPK pathway; between PSPH and SHMT2 in serine biosynthesis; between AKT3 and TSC2 in the PI3K-Akt signaling pathway; and between CRK and RAPGEF1 in the focal adhesion pathway. Our analysis provides evidence that variance in gene expression is an important characteristic of SCZ, and SEM is a promising method for uncovering altered relationships between specific genes thus suggesting affected gene regulation associated with the disease. We identified altered gene-gene interactions in pathways enriched for genes with increased variance in expression in SCZ. These pathways and loci were previously implicated in SCZ, providing further support for the hypothesis that gene expression variance plays important role in the etiology of SCZ.

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Section: Discussionmentioning

confidence: 99%

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Igolkina

Armoskus

Newman

et al. 2018

Front. Mol. Neurosci.

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“…43, 44 In our study, the expression of multiple integrins was altered suggesting a role for miR-137 in the modulation of integrin signaling within the ECM pathway. In neurons, integrin signaling leads to cytoskeletal changes resulting in altered growth cone modulation, neurite outgrowth and axon migration, 45-47 as well as regulation of calcium signaling, 48-50 activation of glutamate receptors, 51 gene transcription, and the release of neurotransmitters. 43 Indeed, neurite outgrowth and axon extension are GO terms being enriched in our dataset, whereas miR-137 was previously experimentally linked to proper AMPAr signaling and presynaptic vesicle release.…”

Section: Discussionmentioning

confidence: 99%

The schizophrenia risk gene MIR137 acts as a hippocampal gene network node orchestrating the expression of genes relevant to nervous system development and function

Loohuis

Kasri²,

Glennon

et al. 2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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MicroRNAs (miRs) are small regulatory molecules, which orchestrate neuronal development and plasticity through modulation of complex gene networks. microRNA-137 (miR-137) is a brain-enriched RNA with a critical role in regulating brain development and in mediating synaptic plasticity. Importantly, mutations in this miR are associated with the pathoetiology of schizophrenia (SZ), and there is a widespread assumption that disruptions in miR-137 expression lead to aberrant expression of gene regulatory networks associated with SZ. To systematically identify the mRNA targets for this miR, we performed miR-137 gain- and loss-of-function experiments in primary rat hippocampal neurons and profiled differentially expressed mRNAs through next-generation sequencing. We identified 500 genes that were bidirectionally activated or repressed in their expression by the modulation of miR-137 levels. Gene ontology analysis using two independent software resources suggested functions for these miR-137-regulated genes in neurodevelopmental processes, neuronal maturation processes and cell maintenance, all of which known to be critical for proper brain circuitry formation. Since many of the putative miR-137 targets identified here also have been previously shown to be associated with SZ, we propose that this miR acts as a critical gene network hub contributing to the pathophysiology of this neurodevelopmental disorder.

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“…Cells derived from schizophrenia patients have been associated with less adhesion and increased motility, 25 and multiple postmortem brain studies of psychiatric disease patients show alterations in the polysialylated neural cell adhesion molecule, 26,27 a protein that has a key role in cell migration. In addition, genome-wide association studies of schizophrenia and BD implicate genes involved in cell adhesion.…”

Section: Discussionmentioning

confidence: 99%

Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness

Wang

Shamah²,

Sun

et al. 2014

Transl Psychiatry

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Development of novel treatments and diagnostic tools for psychiatric illness has been hindered by the absence of cellular models of disease. With the advent of cellular reprogramming, it may be possible to recapitulate the disease biology of psychiatric disorders using patient skin cells transdifferentiated to neurons. However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge. In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6). We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment. This cellular phenotype may represent a useful biomarker to evaluate drug response and screen for novel therapeutics.

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Focal Adhesion Dynamics Are Altered in Schizophrenia

Cited by 70 publications

References 64 publications

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

The schizophrenia risk gene MIR137 acts as a hippocampal gene network node orchestrating the expression of genes relevant to nervous system development and function

Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness

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