Disrupted-in-Schizophrenia-1 expression is regulated by -site amyloid precursor protein cleaving enzyme-1-neuregulin cascade

Departments of Psychiatry, Neuroscience, and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2010; 107(12):5622-7. DOI: 10.1073/pnas.0909284107
Source: PubMed


Neuregulin-1 (NRG1) and Disrupted-in-Schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ErbB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia.

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Available from: Amelia Stanco, Oct 09, 2015
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    • "It can also be inferred from the high co-occurrence of WM-diseases, such as multiple sclerosis (MS), leukodystrophies, and velocardiofacial syndrome, with SZ-like psychoses that OLs and myelin dysfunction may play a key role in neuropsychiatric disease pathophysiology (Baumann et al., 2002; Kosmidis et al., 2010; Walterfang et al., 2005). Despite substantial evidence suggesting the role of OL abnormalities in the pathophysiology of neuropsychiatric diseases, neurobiological studies of these diseases have predominantly focused on neurons whereas only a few reports have studied OLs (Katsel et al., 2011; Seshadri et al., 2010; Wood et al., 2009). We have reported DISC1 binding zinc (DBZ) finger protein, also known as ZNF365 or Su48, is a novel Disrupted-in-schizophrenia 1 (DISC1) binding protein with a predicted C2H2-type zinc-finger motif and coiledcoil domains (Hattori et al., 2007). "
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    ABSTRACT: Recent studies have shown changes in myelin genes and alterations in white matter structure in a wide range of psychiatric disorders. Here we report that DBZ, a central nervous system (CNS)-specific member of the DISC1 interactome, positively regulates the oligodendrocyte (OL) differentiation in vivo and in vitro. In mouse corpus callosum (CC), DBZ mRNA is expressed in OL lineage cells and expression of DBZ protein peaked before MBP expression. In the CC of DBZ-KO mice, we observed delayed myelination during the early postnatal period. Although the myelination delay was mostly recovered by adulthood, OLs with immature structural features were more abundant in adult DBZ-KO mice than in control mice. DBZ was also transiently upregulated during rat OL differentiation in vitro before myelin marker expression. DBZ knockdown by RNA interference resulted in a decreased expression of myelin-related markers and a low number of cells with mature characteristics, but with no effect on the proliferation of oligodendrocyte precursor cells. We also show that the expression levels of transcription factors having a negative-regulatory role in OL differentiation were upregulated when endogenous DBZ was knocked down. These results strongly indicate that OL differentiation in rodents is regulated by DBZ. GLIA 2014.
    Glia 05/2014; 62(5). DOI:10.1002/glia.22636 · 6.03 Impact Factor
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    • "Examples of such brain areas include the bed nucleus of the stria terminalis and the reticular thalamic nucleus (Austin et al., 2004). Although some earlier reports suggested that DISC1 was predominantly expressed in neurons and was largely absent from glia, more recent work has indicated that DISC1 expression may also occur in multiple classes of glial cell in both rodent and human tissue (Seshadri et al., 2010; Kuroda et al., 2011; Ma et al., 2013). Indeed, DISC1 has been implicated in cellular functions of both oligodendrocytes and astrocytes (Katsel et al., 2011; Ma et al., 2013). "
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    ABSTRACT: The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS.
    European Journal of Neuroscience 04/2014; 39(7). DOI:10.1111/ejn.12500 · 3.18 Impact Factor
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    • "Accordingly, a large number of studies have shown the key role of DISC1 in neurons [10]–[19], while only a handful of studies have addressed a possible role of DISC1 in oligodendrocytes [36]–[38]. DISC1 expression in human brain and primary cultured rat cortical oligodendrocytes was shown by Seshadri et al. [37] and a critical requirement for DISC1 in oligodendroglial development, by promoting specification of olig2-positive cells in the hindbrain and other brain regions of zebrafish, was reported by Wood et al [36]. Nevertheless, no study to date, has directly addressed the functional role of DISC1 expressed in a mammalian cell of glial lineage. "
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    ABSTRACT: Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a translocation, t(1;11) (q42.1;q14.3), that segregates with major psychiatric disorders, including schizophrenia, recurrent major depression and bipolar affective disorder, in a Scottish family. Here we report that mammalian DISC1 endogenously expressed in oligodendroglial lineage cells negatively regulates differentiation of oligodendrocyte precursor cells into oligodendrocytes. DISC1 expression was detected in oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA was expressed in primary cultured rat cortical oligodendrocyte precursor cells and decreased when oligodendrocyte precursor cells were induced to differentiate by PDGF deprivation. Immunocytochemical analysis showed that overexpressed DISC1 was localized in the cell bodies and processes of oligodendrocyte precursor cells and oligodendrocytes. We show that expression of the myelin related markers, CNPase and MBP, as well as the number of cells with a matured oligodendrocyte morphology, were decreased following full length DISC1 overexpression. Conversely, both expression of CNPase and the number of oligodendrocytes with a mature morphology were increased following knockdown of endogenous DISC1 by RNA interference. Overexpression of a truncated form of DISC1 also resulted in an increase in expression of myelin related proteins and the number of mature oligodendrocytes, potentially acting via a dominant negative mechanism. We also identified involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of oligodendrocyte differentiation, both well-known transcription factors involved in the regulation of myelin genes.
    PLoS ONE 02/2014; 9(2):e88506. DOI:10.1371/journal.pone.0088506 · 3.23 Impact Factor
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