Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways

Panaccione, Isabella; Napoletano, Flavia; Forte, Alberto; Kotzalidis, Georgios D.; Casale, Antonio Del; Rapinesi, Chiara; Brugnoli, Chiara; Serata, Daniele; Caccia, Federica; Cuomo, Ilaria; Ambrosi, Elisa; Simonetti, Alessio; Savoja, Valeria; Chiara, Lavinia De; Danese, Emanuela; Manfredi, Giovanni; Janiri, Delfina; Motolese, Marta; Nicoletti, Ferdinando; Girardi, Paolo; Sani, Gabriele

doi:10.2174/1570159x113119990037

Cited by 42 publications

(31 citation statements)

References 296 publications

(294 reference statements)

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“…In addition to pathways enriched in differentially expressed genes (Wnt, Notch, Serine biosynthesis; Evgrafov et al, 2017), we found that PI3K-Akt signaling has been identified as important in multiple studies of SCZ (Mao et al, 2009; Panaccione et al, 2013; Singh et al, 2013; Topol et al, 2015; Mulligan and Cheyette, 2016; Howell et al, 2017; Wang et al, 2017). Pathway analysis of GWAS data, performed by The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium (2015) showed enrichment of several GO terms, associated with neuron structure and histone H3-K4 methylation.…”

Section: Methodsmentioning

confidence: 72%

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: Methodsmentioning

confidence: 72%

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Igolkina

Armoskus

Newman

et al. 2018

Front. Mol. Neurosci.

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“…The most consistent abnormalities associated with antipsychotic response are Akt1, glycogen synthase kinase3beta and beta-catenin pathways [70]. VEGF is associated with inflammation reaction.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia

Lee

Huang

2016

BMC Med Genomics

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BackgroundEpigenetics of schizophrenia provides important information on how the environmental factors affect the genetic architecture of the disease. DNA methylation plays a pivotal role in etiology for schizophrenia. Previous studies have focused mostly on the discovery of schizophrenia-associated SNPs or genetic variants. As postmortem brain samples became available, more and more recent studies surveyed transcriptomics of the diseases. In this study, we constructed protein-protein interaction (PPI) network using the disease associated SNP (or genetic variants), differentially expressed disease genes and differentially methylated disease genes (or promoters). By combining the different datasets and topological analyses of the PPI network, we established a more comprehensive understanding of the development and genetics of this devastating mental illness.ResultsWe analyzed the previously published DNA methylation profiles of prefrontal cortex from 335 healthy controls and 191 schizophrenic patients. These datasets revealed 2014 CpGs identified as GWAS risk loci with the differential methylation profile in schizophrenia, and 1689 schizophrenic differential methylated genes (SDMGs) identified with predominant hypomethylation. These SDMGs, combined with the PPIs of these genes, were constructed into the schizophrenic differential methylation network (SDMN). On the SDMN, there are 10 hypermethylated SDMGs, including GNA13, CAPNS1, GABPB2, GIT2, LEFTY1, NDUFA10, MIOS, MPHOSPH6, PRDM14 and RFWD2. The hypermethylation to differential expression network (HyDEN) were constructed to determine how the hypermethylated promoters regulate gene expression. The enrichment analyses of biochemical pathways in HyDEN, including TNF alpha, PDGFR-beta signaling, TGF beta Receptor, VEGFR1 and VEGFR2 signaling, regulation of telomerase, hepatocyte growth factor receptor signaling, ErbB1 downstream signaling and mTOR signaling pathway, suggested that the malfunctioning of these pathways contribute to the symptoms of schizophrenia.ConclusionsThe epigenetic profiles of DNA differential methylation from schizophrenic brain samples were investigated to understand the regulatory roles of SDMGs. The SDMGs interplays with SCZCGs in a coordinated fashion in the disease mechanism of schizophrenia. The protein complexes and pathways involved in SDMN may be responsible for the etiology and potential treatment targets. The SDMG promoters are predominantly hypomethylated. Increasing methylation on these promoters is proposed as a novel therapeutic approach for schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0229-y) contains supplementary material, which is available to authorized users.

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“…However, alterations of Wnt canonical signaling pathway functionally lead to diverse neuropathologies and neurodevelopmental dysfunctions, such as altered synaptic plasticity, that have been reviewed by Inestrosa et al (2015) and Tang et al (2014) . Indeed, Wnt signaling pathway dysfunctions are involved in the etiopathogenesis of various neurological diseases such as chronic pain, cerebral ischemia, Huntington disease, amyotrophic lateral sclerosis and other neurodegenerative pathologies . Wnt alterations in schizophrenia could be through roles of this signaling pathway in neuronal migration, survival, and/or apoptosis .…”

Section: Discussionmentioning

confidence: 99%

Dental and extra‐oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype–phenotype study

et al. 2017

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WNT10A gene encodes a canonical wingless pathway signaling molecule involved in cell fate specification as well as morphogenetic patterning of the developing ectoderm, nervous system, skeleton, and tooth. In patients, WNT10A mutations are responsible for ectodermal-derived pathologies including isolated hypo-oligodontia, tricho-odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome (SSPS). Here we describe the dental, ectodermal, and extra-ectodermal phenotypic features of a cohort of 41 patients from 32 unrelated families. Correlations with WNT10A molecular status (heterozygous carrier, compound heterozygous, homozygous) and patient's phenotypes were performed. Mild to severe oligodontia was observed in all patients bearing biallelic WNT10A mutations. However, patients with compound heterozygous mutations presented no significant difference in phenotypes compared with homozygous individuals. Anomalies in tooth morphology were frequently observed with heterozygous patients displaying hypodontia. No signs of SSPS, especially eyelids cysts, were detected in our cohort. Interestingly, extra-ectodermal signs consisted of skeletal, neurological and vascular anomalies, the latter suggesting a wider phenotypic spectrum associated with WNT10A mutations. Indeed, the Wnt pathway plays a crucial role in skeletal development, lipid metabolism, and neurogenesis, potentially explaining patient's clinical manifestations.

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Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways

Cited by 42 publications

References 296 publications

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia

Dental and extra‐oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype–phenotype study

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