| 1 | Neuropsychopharmacology 2008 Nov 33: 2993-3009 |
|---|---|
| PMID | 18322470 |
| Title | Abnormal indices of cell cycle activity in schizophrenia and their potential association with oligodendrocytes. |
| Abstract | The goal of this study was to determine what signaling pathways may elicit myelin-specific gene expression deficits in schizophrenia (SZ). Microarray analyses indicated that genes associated with canonical cell cycle pathways were significantly affected in the anterior cingulate gyrus (ACG), the region exhibiting the most profound myelin-specific gene expression changes, in persons with SZ (N=16) as compared with controls (N=19). Detected gene expression changes of key regulators of G1/S phase transition and genes central to oligodendrocyte differentiation were validated using qPCR in the ACG in an independent cohort (Ns=45/34). The relative abundance of phosphorylated retinoblastoma protein (pRb) was increased in the white matter underlying the ACG in SZ subjects (Ns=12). The upregulation of cyclin D1 gene expression and the downregulation of p57(Kip2), accompanied by increased cyclin D/CDK4-dependent phosphorylation of pRb, acting as a checkpoint for G1/S phase transition, suggest abnormal cell cycle re-entry in postmitotic oligodendrocytes in SZ. Furthermore, gene expression profiling of brain samples from myelin mutant animal models, quaking and myelin-associated glycoprotein (MAG) null mice, showed that cell cycle gene expression changes were not a necessary consequence of the reduced gene expression of structural myelin proteins, such as MAG. While, quaking, a known modulator of cell cycle activity during oligodendrocyte differentiation impairs the expression of multiple myelin genes, including those that are affected in SZ. These data suggest that the normal patterns of cell cycle gene and protein expression are disrupted in SZ and that this disruption may contribute to the oligodendroglial deficits observed in SZ. |
| SCZ Keywords | schizophrenia |
| 2 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2016 May 70: 85-91 |
| PMID | 27216283 |
| Title | The cell cycle-related genes as biomarkers for schizophrenia. |
| Abstract | Recent studies suggest that genomic abnormalities such as single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) may elevate the risk of schizophrenia. Such genomic abnormalities often occur during chromosomal DNA replication in the S phase of cell cycle. In addition, several studies showed that abnormal expressions of several cell cycle-related genes are associated with schizophrenia. Therefore, here we compared mRNA expression levels of cell cycle-related genes in peripheral blood cells between patients with schizophrenia and healthy controls. mRNA expression levels of cell cycle-related genes in peripheral blood cells from patients with schizophrenia and healthy controls were measured with quantitative reverse transcription polymerase chain reaction (Q-RT-PCR). The discovery, replication and intervention studies with Q-RT-PCR were performed as follows: discovery (40 cases and 20 controls), replication (82 cases and 74 controls) and intervention (22 cases and 18 controls). Nine genes were identified in the discovery and replication stages as schizophrenia-associated genes. Moreover, the combination of mRNA expression levels of CDK4, MCM7 and POLD4 was identified as a potential biomarker for schizophrenia with multivariate logistic regression analysis. The intervention stage revealed that the mRNA expression levels of these three genes were significantly decreased in the acute state of schizophrenia, and CDK4 was significantly recovered in the remission state of schizophrenia. The combination of mRNA expression levels of three cell cycle-related genes such as CDK4, MCM7 and POLD4 is expected to be a candidate for useful biomarkers for schizophrenia. Especially, the mRNA expression changes of CDK4 may be potential as both trait and state markers for schizophrenia. |
| SCZ Keywords | schizophrenia |
| 3 | Biochim. Biophys. Acta 2016 Aug 1862: 1383-91 |
| PMID | 27130439 |
| Title | Schizophrenia susceptibility gene product dysbindin-1 regulates the homeostasis of cyclin D1. |
| Abstract | Dysbindin-1 (dystrobrevin binding protein-1, DTNBP1) is now widely accepted as a potential schizophrenia susceptibility gene and accumulating evidence indicates its functions in the neural development. In this study, we tried to identify new binding partners for dysbindin-1 to clarify the novel function of this molecule. When consulted with BioGRID protein interaction database, cyclin D3 was found to be a possible binding partner for dysbindin-1. We then examined the interaction between various dysbindin-1 isoforms (dysbindin-1A, -1B and -1C) and all three D-type cyclins (cyclin D1, D2, and D3) by immunoprecipitation with the COS7 cell expression system, and found that dysbindin-1A preferentially interacts with cyclin D1. The mode of interaction between these molecules was considered as direct binding since recombinant dysbindin-1A and cyclin D1 formed a complex in vitro. Mapping analyses revealed that the C-terminal region of dysbindin-1A binds to the C-terminal of cyclin D1. Consistent with the results of the biochemical analyses, endogenous dysbindin-1was partially colocalized with cyclin D1 in NIH3T3 fibroblast cells and in neuronal stem and/or progenitor cells in embryonic mouse brain. While co-expression of dysbindin-1A with cyclin D1 changed the localization of the latter from the nucleus to cytosol, cyclin D1-binding partner CDK4 inhibited the dysbindin-cyclin D1 interaction. Meanwhile, depletion of endogenous dysbindin-1A increased cyclin D1 expression. These results indicate that dysbindin-1A may control the cyclin D1 function spatiotemporally and might contribute to better understanding of the pathophysiology of dysbindin-1-associated disorders. |
| SCZ Keywords | schizophrenia |