Prefrontal Abnormality of Schizophrenia Revealed by DNA Microarray: Impact on Glial and Neurotrophic Gene Expression

Sugai, Tetsuji; Kawamura, Minoru; Iritani, Shuji; Araki, Kazuo; Makifuchi, Takao; Imai, China; Nakamura, Ryosuke; Kakita, Akiyoshi; Takahashi, Hitoshi; Nawa, Hiroyuki

doi:10.1196/annals.1316.011

Cited by 106 publications

(50 citation statements)

References 17 publications

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“…One of the most widely replicated groups of genes with altered expression in schizophrenia relate to oligodendrocyte function and myelination, oligodendrocytes being the myelinating cells in the brain (3)(4)(5)(7)(8)(9)(10)(11)(12). These data are compatible with the considerable evidence for altered myelination and oligodendrocyte function in schizophrenia (13).…”

supporting

confidence: 78%

Convergent evidence that oligodendrocyte lineage transcription factor 2 ( OLIG2 ) and interacting genes influence susceptibility to schizophrenia

Georgieva

Moskvina

Peirce

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

111

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Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n ‫؍‬ Ϸ1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P ‫؍‬ 0.0001, genewide P ‫؍‬ 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P ‫؍‬ 0.0001, corrected P ‫؍‬ 0.008) for interaction with ERBB4 (minimum P ‫؍‬ 0.002, corrected P ‫؍‬ 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10 ؊7 ) and ERBB4 (P ‫؍‬ 0.002, corrected P ‫؍‬ 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function. association ͉ oligodentrocyte͞myelin-related genes S chizophrenia is a major psychiatric disorder characterized by disturbances of perception, emotion, social functioning, and cognition. Its etiology includes a strong heritable component (1), but despite some successes in identifying susceptibility genes (2) the fundamental pathophysiology remains uncertain.Global surveys of mRNA expression can offer insights into potential pathophysiological pathways, even in tissues as complex as postmortem human brain. A prominent example is the identification of altered expression of ERBB3 in schizophrenia by independent groups (3-5), a finding of likely pathophysiological relevance given that its ERBB3 is one of two receptors that directly bind neuregulin 1, whose cognate gene (NRG1) is strongly implicated as a susceptibility gene for schizophrenia (2, 6).One of the most widely replicated groups of genes with altered expression in schizophrenia relate to oligodendrocyte function and myelination, oligodendrocytes being the myelinating cells in the brain (3)(4)(5)(7)(8)(9)(10)(11)(12). These data are compatible with the considerable evidence for altered myelination and oligodendrocyte function in schizophrenia (13). There is therefore a strong rationale to target for genetic analysis oligodendrocyte͞myelination related (OMR) genes. Here, we report strong data concerning a key OMR target, oligodendrocyte lineage transcription factor 2 (OLIG2).OLIG2 is a basi...

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supporting

confidence: 78%

Convergent evidence that oligodendrocyte lineage transcription factor 2 ( OLIG2 ) and interacting genes influence susceptibility to schizophrenia

Georgieva

Moskvina

Peirce

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Several postmortem studies in schizophrenia have demonstrated reduced expression of oligodendrocyte-related genes, [17][18][19][20][21][67][68][69][70][71][72] some of which may be susceptibility genes for schizophrenia. 33,[72][73][74][75] Moreover, several studies have evidence for deficits in oligodendrocytes in the disorder.…”

Section: Discussionmentioning

confidence: 99%

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

et al. 2007

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Neuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase b/f (RPTPb), we postulated that simultaneous binding of MAGI proteins to RPTPb and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPb. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPb for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n = B1400). PTPRZ1, which codes for RPTPb, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P = 0.0003; gene-wide P = 0.0064; hypothesiswide P = 0.026). The data provide evidence for a role of PTPRZ1, and for RPTPb signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPb in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia.

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“…119,120 Consistent evidence for an oligodendrocyte dysfunction in the disease also emerged from two other studies, in which levels of gene expression were assessed in the prefrontal cortices of schizophrenic patients. 121,118 Tkachev et al 118 further reported significant downregulation of proteolipid protein1 (PLP1), which maps at chromosome Xq21.3-q22 and mediates axonal-glial interactions, oligodendrocyte transmembrane protein (CLDN11), which is the third most abundant myelin protein in the CNS after PLP1 and myelin basic protein (MBP). MBP was also found to be downregulated.…”

Section: Oligodendrocyte-related Genes Associated With Schizophreniamentioning

confidence: 99%

The myelin-pathogenesis puzzle in schizophrenia: a literature review

2007

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Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible genes and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of chromosomes and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single locus or gene, leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder.

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Prefrontal Abnormality of Schizophrenia Revealed by DNA Microarray: Impact on Glial and Neurotrophic Gene Expression

Cited by 106 publications

References 17 publications

Convergent evidence that oligodendrocyte lineage transcription factor 2 ( OLIG2 ) and interacting genes influence susceptibility to schizophrenia

Convergent evidence that oligodendrocyte lineage transcription factor 2 ( OLIG2 ) and interacting genes influence susceptibility to schizophrenia

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

The myelin-pathogenesis puzzle in schizophrenia: a literature review

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