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

Georgieva, Lyudmila; Moskvina, Valentina; Peirce, T.; Norton, Nadine; Bray, Nicholas John; Jones, Lesley; Holmans, Peter Alan; MacGregor, Stuart; Zammit, Stanley; Wilkinson, J.; Williams, Hywel; Nikolov, Ivan; Williams, Nigel; Ivanov, Dobril; Davis, Kenneth L.; Haroutunian, Vahram; Buxbaum, Joseph D.; Craddock, Nick; Kirov, George; Owen, Michael John; O’Donovan, Michael

doi:10.1073/pnas.0603029103

Cited by 111 publications

(108 citation statements)

References 53 publications

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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. [76][77][78][79] These oligodendrocyte abnormalities may in turn contribute to the loss of coherence of axon tracts, and reduced connectivity, in schizophrenia.…”

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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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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“…N euregulin 1 (NRG1), a growth factor essential for brain development, and erbB4, one of its receptors, are genetically linked to schizophrenia and bipolar disorder (1)(2)(3)(4). A role for NRG1-erbB receptor signaling in psychiatric diseases is also supported by studies showing that expression levels or function of NRG1, erbB3, and erbB4 are altered in patient tissues (1,4,5).…”

mentioning

confidence: 81%

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

Roy

Murtie

El-Khodor

et al. 2007

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

294

238

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Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.dopamine ͉ erbB receptor ͉ neuregulin ͉ schizophrenia ͉ white matter N euregulin 1 (NRG1), a growth factor essential for brain development, and erbB4, one of its receptors, are genetically linked to schizophrenia and bipolar disorder (1-4). A role for NRG1-erbB receptor signaling in psychiatric diseases is also supported by studies showing that expression levels or function of NRG1, erbB3, and erbB4 are altered in patient tissues (1,4,5). Moreover, mice with reduced levels of NRG1 or erbB4 exhibit behavioral alterations relevant to mental illness (6-9). Although the evidence linking this pathway and psychiatric disorders is strong, the mechanisms by which it contributes to these diseases remain unknown. NRG1-erbB signaling is important in neurons, astrocytes, and oligodendrocytes (OLs), but the specific cell types through which altered NRG1-erbB signaling contributes to these disorders is undefined.Significant alterations in white matter are found in schizophrenia, bipolar disorder, major depression, anxiety, and obsessivecompulsive disorder (10-14), and genes expressed by OLs have been linked with some of these diseases (15, 16). Interestingly, NRG1-erbB signaling regulates OL development in vitro (17), although this has not been shown in the intact organism.To determine whether erbB signaling plays a role in CNS myelination and whether disruption of this pathway in OLs produces defects related to human psychiatric disorders, we analyzed mice in which erbB signaling in OLs is blocked by expression of a dominant negative erbB receptor (DN-erbB4) (18). We show that alterations in erbB signaling lead to changes in OL morphology, number, and function in vivo. Moreover, these transgenic (Tg) mice have increased levels of functional dopamine transporters (DAT) and D1 receptors and exhibit behavioral alterations suggestive of neuropsychiatric disorders. Together, these results indicate that altered NRG1-erbB signaling in OLs may be a potential contributor to the pathogenesis of mental illness....

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“…A single-nucleotide polymorphism that does not alter the amino-acid sequence of CNPase, but rather decreases its expression levels, has been suggested to play a role in schizophrenia [43][44][45][46][47][48][49][50][51][52][53][54] .…”

Section: Cnpase In Health and Diseasementioning

confidence: 99%

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

Raasakka

Kursula

2014

Neurosci. Bull.

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The membrane-anchored myelin enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) was discovered in the early 1960s and has since then troubled scientists with its peculiar catalytic activity and high expression levels in the central nervous system. Despite decades of research, the actual physiological relevance of CNPase has only recently begun to unravel. In addition to a role in myelination, CNPase is also involved in local adenosine production in traumatic brain injury and possibly has a regulatory function in mitochondrial membrane permeabilization. Although research focusing on the CNPase phosphodiesterase activity has been helpful, several open questions concerning the protein function in vivo remain unanswered. This review is focused on past research on CNPase, especially in the fields of structural biology and enzymology, and outlines the current understanding regarding the biochemical and physiological signifi cance of CNPase, providing ideas and directions for future research.Keywords: 2′,3′-cyclic nucleotide 3′-phosphodiesterase; calmodulin; central nervous system; cytoskeleton; myelin proteins; RNA ·Review· IntroductionMyelin is a specialized multilamellar structure, which is wrapped around neuronal axons by oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). The membrane sheets of myelin are densely packed, resulting in the extrusion of cytosolic elements and in the formation of a lipid-rich, insulating sheath that enables the acceleration of nerve impulses. A mature myelin sheath can be morphologically divided into compact and non-compact myelin, of which the latter has a higher cytosolic content and further contains several subcompartments, such as the abaxonal and adaxonal layers, as well as the paranodal loops [1,2] .Myelin contains a set of unique proteins that generally display strict localization to either compact or non-compact myelin, which is thought to be at least partially driven by size exclusion [3,4] . The myelin environment being low in aqueous content and harboring negatively charged, tightly packed membrane interfaces, myelin proteins typically exhibit attributes such as strong hydrophobicity, peripheral membrane association, transmembrane domains, and a high positive net charge, as well as intrinsic disorder [5] .Several myelin proteins have delicately regulated expression levels and functions. Past research using cell culture and animal models have outlined the importance of various proteins in demyelination -a situation where myelin undergoes morphological changes and loss [6] .Demyelination causes neurological disorders, including multiple sclerosis (MS), Charcot-Marie-Tooth disease, and leukodystrophies, such as Pelizaeus-Merzbacher disease [7][8][9][10] .2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase)is one of the most abundant proteins in CNS myelin and a possible auto-antigen in MS [4,11] . The high expression levels of CNPase, together with its rather unusual enzymatic after the initial di...

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

Cited by 111 publications

References 53 publications

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

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

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

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