Abnormalities of WNT signalling in schizophrenia—Evidence for neurodevelopmental abnormality

Vrije Universiteit Brussel, Bruxelles, Brussels Capital, Belgium
Neuroreport (Impact Factor: 1.52). 06/1998; 9(7):1379-83. DOI: 10.1097/00001756-199805110-00024
Source: PubMed


The Wnt signalling pathway is central to normal brain development in vertebrates and invertebrates and mediates cell fate determination, cell adhesion and cell proliferation. However, its relevance to disorders of cerebral development in man is untested. We evaluated the potential involvement of the Wnt signalling pathway in schizophrenia, a disorder of neurodevelopment origin in which alterations in neuronal lamination and orientation have been described. Using immunohistochemistry and semi-quantitative rating scales, we examined the distribution of two components of the Wnt signalling pathway, beta-catenin and gamma-catenin in the hippocampus and subiculum of 12 schizophrenic (DSMIIR criteria) and 14 control subjects. Both catenins were distributed as intraneuronal diffuse and/or ring shaped forms. The diffuse staining of both forms catenin were reduced in the CA3 and beta-catenin was also reduced in the CA4 hippocampal subregion among schizophrenic subjects. These alternations may represent the basis of the developmental brain abnormalities found in schizophrenia and would have functionally important consequences in the adult.

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    • "However, our results are aligned with those of Emamian and associates [9] who reported decreased phosphorylation of GSK3B at Ser9 in peripheral lymphocytes and frontal cortex of individuals with schizophrenia, suggesting increased GSK3B activity. Our results are further supported by numerous in vitro studies demonstrating that disheveled homologues, such as DVL2, inhibit GSK3B phosphorylation of beta-catenin [10, 11] as well as work carried out within our laboratory demonstrating reduced levels of beta-catenin in the hippocampus of schizophrenic subjects [12], indicative of increased activity of GSK3B. However, contrary findings have been reported by us and others showing no difference in GSK3B mRNA levels in lymphocytes [13] and protein levels in the prefrontal cortex [14] compared to controls. "
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    ABSTRACT: Genes in the Wnt (wingless)/ β -catenin signaling pathway have been implicated in schizophrenia pathogenesis. No study has examined this pathway in the broader context of psychosis symptom severity. We investigated the association between symptom severity scores and expression of 25 Wnt pathway genes in blood from 19 psychotic patients. Significant correlations between negative symptom scores and deshivelled 2 (DVL2) (r adj = -0.70; P = 0.0008) and glycogen synthase kinase 3 beta (GSK3B) (r adj = 0.48; P = 0.039) were observed. No gene expression levels were associated with positive symptoms. Our findings suggest that the Wnt signaling pathway may harbor biomarkers for severity of negative but not positive symptoms.
    Full-text · Article · Nov 2013
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    • "), WNT signaling pathway (P-value 5.9 Â 10 À3 ) and cell adhesion/synaptic contact (P-value 3.0 Â 10 À3 ) (Supplementary Table VII). It is interesting that some of them have been previously associated with schizophrenia, such as the WNT signaling pathway [Cotter et al., 1998; Miyaoka et al., 1999; Freyberg et al., 2010] and cell adhesion/synaptic contact [Vawter, 2000; Gross et al., 2003; Eastwood, 2004; Stephan et al., 2009; Hayashi-Takagi and Sawa, 2010; O'Dushlaine et al., 2011]. "
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    ABSTRACT: Common SNPs in the transcription factor 4 (TCF4; ITF2, E2-2, SEF-2) gene, which encodes a basic Helix-Loop-Helix (bHLH) transcription factor, are associated with schizophrenia, conferring a small increase in risk. Other common SNPs in the gene are associated with the common eye disorder Fuch's corneal dystrophy, while rare, mostly de novo inactivating mutations cause Pitt-Hopkins syndrome. In this review, we present a systematic bioinformatics and literature review of the genomics, biological function and interactome of TCF4 in the context of schizophrenia. The TCF4 gene is present in all vertebrates, and although protein length varies, there is high conservation of primary sequence, including the DNA binding domain. Humans have a unique leucine-rich nuclear export signal. There are two main isoforms (A and B), as well as complex splicing generating many possible N-terminal amino acid sequences. TCF4 is highly expressed in the brain, where plays a role in neurodevelopment, interacting with class II bHLH transcription factors Math1, HASH1, and neuroD2. The Ca(2+) sensor protein calmodulin interacts with the DNA binding domain of TCF4, inhibiting transcriptional activation. It is also the target of microRNAs, including mir137, which is implicated in schizophrenia. The schizophrenia-associated SNPs are in linkage disequilibrium with common variants within putative DNA regulatory elements, suggesting that regulation of expression may underlie association with schizophrenia. Combined gene co-expression analyses and curated protein-protein interaction data provide a network involving TCF4 and other putative schizophrenia susceptibility genes. These findings suggest new opportunities for understanding the molecular basis of schizophrenia and other mental disorders. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · Jan 2013 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "Several WNTs are expressed in the VMB where they regulate the birth of DA neurons [58] and play an important role in dopamine related adult brain functions [59]. Abnormalities of Wnt signaling are implicated in AD [38], PD [60], [61], schizophrenia [62], and frontotemporal dementia [63]. In our study, we observed a down-regulation of the Wnt gene expression in VMB and STR including Wnt1, Wnt2, Wnt3, Wnt4, Wnt5a, Wnt6, Wnt7a, Wnt7b, Wnt10a and Wnt10. "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease in which the etiology of 90 percent of the patients is unknown. Pesticide exposure is a major risk factor for PD, and paraquat (PQ), pyridaben (PY) and maneb (MN) are amongst the most widely used pesticides. We studied mRNA expression using transcriptome sequencing (RNA-Seq) in the ventral midbrain (VMB) and striatum (STR) of PQ, PY and paraquat+maneb (MNPQ) treated mice, followed by pathway analysis. We found concordance of signaling pathways between the three pesticide models in both the VMB and STR as well as concordance in these two brain areas. The concordant signaling pathways with relevance to PD pathogenesis were e.g. axonal guidance signaling, Wnt/β-catenin signaling, as well as pathways not previously linked to PD, e.g. basal cell carcinoma, human embryonic stem cell pluripotency and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Human PD pathways previously identified by expression analysis, concordant with VMB pathways identified in our study were axonal guidance signaling, Wnt/β-catenin signaling, IL-6 signaling, ephrin receptor signaling, TGF-β signaling, PPAR signaling and G-protein coupled receptor signaling. Human PD pathways concordant with the STR pathways in our study were Wnt/β-catenin signaling, axonal guidance signaling and G-protein coupled receptor signaling. Peroxisome proliferator activated receptor delta (Ppard) and G-Protein Coupled Receptors (GPCRs) were common genes in VMB and STR identified by network analysis. In conclusion, the pesticides PQ, PY and MNPQ elicit common signaling pathways in the VMB and STR in mice, which are concordant with known signaling pathways identified in human PD, suggesting that these pathways contribute to the pathogenesis of idiopathic PD. The analysis of these networks and pathways may therefore lead to improved understanding of disease pathogenesis, and potential novel therapeutic targets.
    Full-text · Article · May 2012 · PLoS ONE
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