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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    • "The studies from the Sive and Morris laboratories showed roles for disc1 in embryonic neurogenesis and neural crest migration/differentiation respectively, while our studies revealed a novel requirement for disc1 in the specification of oligodendrocyte precursor cells in the hindbrain (Wood et al., 2009). Subsequent studies have supported an important role for DISC1 in oligodendrocyte development in higher vertebrates (Hattori et al., 2014; Katsel et al., 2011; Seshadri et al., 2010; Shimizu et al., 2014), while interrogation of a CNS cell types exon array (Cahoy et al., 2008) by us revealed that among the CNS cell types analysed, Disc1 was most highly expressed in OPCs. DISC1 has also been implicated in agenesis of the corpus callosum in humans (Osbun et al., 2011). "
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    ABSTRACT: DISRUPTED-IN-SCHIZOPHRENIA (DISC1) has been one of the most intensively studied genetic risk factors for mental illness since it was discovered through positional mapping of a translocation breakpoint in a large Scottish family where a balanced chromosomal translocation was found to segregate with schizophrenia and affective disorders. While the evidence for it being central to disease pathogenesis in the original Scottish family is compelling, recent genome-wide association studies have not found evidence for common variants at the DISC1 locus being associated with schizophrenia in the wider population. It may therefore be the case that DISC1 provides an indication of biological pathways that are central to mental health issues and functional studies have shown that it functions in multiple signalling pathways. However, there is little information regarding factors that function upstream of DISC1 to regulate its expression and function. We herein demonstrate that Sonic hedgehog (Shh) signalling promotes expression of disc1 in the zebrafish brain. Expression of disc1 is lost in smoothened mutants that have a complete loss of Shh signal transduction, and elevated in patched mutants which have constitutive activation of Shh signalling. We previously demonstrated that disc1 knockdown has a dramatic effect on the specification of oligodendrocyte precursor cells (OPC) in the hindbrain and Shh signalling is known to be essential for the specification of these cells. We show that disc1 is prominently expressed in olig2-positive midline progenitor cells that are absent in smo mutants, while cyclopamine treatment blocks disc1 expression in these cells and mimics the effect of disc1 knock down on OPC specification. Various features of a number of psychiatric conditions could potentially arise through aberrant Hedgehog signalling. We therefore suggest that altered Shh signalling may be an important neurodevelopmental factor in the pathobiology of mental illness.
    Biology Open 09/2015; DOI:10.1242/bio.012005 · 2.42 Impact Factor
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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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