| 1 | Hum. Genet. 2005 Oct 117: 520-7 |
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| PMID | 16021468 |
| Title | Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson's disease. |
| Abstract | We previously identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PHOX2B (PMX2B), the gene for a transcription factor that plays important roles in the development of oculomotor nerves and catecholaminergic neurons and regulates the expression of both tyrosine hydroxylase and dopamine beta-hydroxylase genes. An association was detected between gene polymorphisms and overall schizophrenia, and more specifically, schizophrenia with ocular misalignment. These prior results implied the existence of other schizophrenia susceptibility genes that interact with PHOX2B to increase risk of the combined phenotype. ASCL1 was considered as a candidate interacting partner of PHOX2B, as ASCL1 is a transcription factor that co-regulates catecholamine-synthesizing enzymes with PHOX2B. The genetic contributions of PHOX2B and ASCL1 were examined separately, along with epistatic interactions with broader candidate phenotypes. These phenotypes included not only schizophrenia, but also bipolar affective disorder and Parkinson's disease (PD), each of which involve catecholaminergic function. The current case-control analyses detected nominal associations between polyglutamine length variations in ASCL1 and PD (P=0.018), but supported neither the previously observed weak association between PHOX2B and general schizophrenia, nor other gene-disease correlations. Logistic regression analysis revealed the effect of ASCL1 dominant x PHOX2B additive (P=0.008) as an epistatic gene-gene interaction increasing risk of PD. ASCL1 controls development of the locus coeruleus (LC), and accumulating evidence suggests that the LC confers protective effects against the dopaminergic neurodegeneration inherent in PD. The present genetic data may thus suggest that polyglutamine length polymorphisms in ASCL1 could influence predispositions to PD through the fine-tuning of LC integrity. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Schizophr. Res. 2006 Dec 88: 275-82 |
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| PMID | 16899352 |
| Title | Analysis of coding-polymorphisms in NOTCH-related genes reveals NUMBL poly-glutamine repeat to be associated with schizophrenia in Brazilian and Danish subjects. |
| Abstract | Abnormality in neurodevelopment is one of the most robust hypotheses on the etiology of schizophrenia and has found substantial support from brain imaging and genetic studies. Neurodevelopmental processes involve several signaling pathways, including the Notch, but little is known at present regarding their possible involvement in schizophrenia. In the present study we investigated the link of non-synonymous variants of five genes of the Notch pathway (NOTCH2, NOTCH3, JAGGED2, ASCL1 and NUMBL) to schizophrenia in a group of 200 Brazilian patients and 200-paired controls. Also, we replicated the association of the NUMBL variant, our most promising finding, in an unrelated set of 684 Danish patients and controls. When the Brazilian and Danish cohorts were merged, a total of 1084 subjects, we found the allele 18 CAG of NUMBL (p=0.003, x2=8.88, OR=1.30, 95% CI 1.09-1.56) as well as the 18/18 CAG genotype (p=0.002, x2=9.46, OR=1.46, 95% CI 1.15-1.87) to be associated with schizophrenia. The consistency of this finding in two independent and unrelated populations reinforces the veracity of this association. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | PLoS ONE 2010 -1 5: e8596 |
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| PMID | 20062533 |
| Title | Increased stathmin1 expression in the dentate gyrus of mice causes abnormal axonal arborizations. |
| Abstract | Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in multiple brain functions. To clarify the cause of abnormal behavior in PACAP deficient-mice, we attempted the identification of genes whose expression was altered in the dentate gyrus of PACAP-deficient mice using the differential display method. Expression of stathmin1 was up-regulated in the dentate gyrus at both the mRNA and protein levels. PACAP stimulation inhibited stathmin1 expression in PC12 cells, while increased stathmin1expression in neurons of the subgranular zone and in primary cultured hippocampal neurons induced abnormal arborization of axons. We also investigated the pathways involved in PACAP deficiency. ASCL1 binds to E10 box of the stathmin1 promoter and increases stathmin1 expression. Inhibitory bHLH proteins (Hes1 and Id3) were rapidly up-regulated by PACAP stimulation, and Hes1 could suppress ASCL1 expression and Id3 could inhibit ASCL1 signaling. We also detected an increase of stathmin1 expression in the brains of schizophrenic patients. These results suggest that up-regulation of stathmin1 in the dentate gyrus, secondary to PACAP deficiency, may create abnormal neuronal circuits that cause abnormal behavior. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Eur. J. Neurosci. 2011 Dec 34: 1906-22 |
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| PMID | 22132705 |
| Title | The genetic signature of perineuronal oligodendrocytes reveals their unique phenotype. |
| Abstract | Oligodendrocytes--best known for assembling central nervous system myelin--can be categorized as precursors, myelin-forming cells and non-myelinating perineuronal cells. Perineuronal oligodendrocytes have been well characterized morphologically and ultrastructurally, but knowledge about their function remains scanty. It has been proposed that perineuronal oligodendrocytes support neurons and, following injury, transform into myelin-synthesizing cells. Recent findings implicating perineuronal oligodendrocytes in cytoarchitectural abnormalities in the prefrontal cortex of schizophrenia and other psychiatric disorders shed new light on these cells. We have obtained the genetic signature of perineuronal oligodendrocytes by identifying gene expression differences between oligodendrocyte subpopulations using cell-specific tags, microarray technology, quantitative time-resolved polymerase chain reaction and bioinformatics tools. We show that perineuronal cells are the progeny of oligodendrocyte progenitors and, hence, are members of the oligodendrocyte lineage. Physiologically they exhibit a novel phenotype. Their expression of PDGFR-?? and its growth factor ligand PDGF-CC sets them apart from members of their lineage as this receptor precludes their response to the same growth factors that act on myelinating cells. Their coordinate expression and context-specific usage of transcription factors Olig2, ASCL1 and Pax6, together with the prominent presence of transcription factors Pea3, Lhx2 and Otx2--not hitherto linked to the oligodendrocyte lineage--suggested a cell with features that blur the boundary between a neuron and a glial cell. But they also maintain a reservoir of untranslated transcripts encoding major myelin proteins presumably for a demyelinating episode. This first molecular characterization of perineuronal oligodendrocytes revealed the striking difference between the myelinating and non-myelinating phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | PLoS ONE 2013 -1 8: e73169 |
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| PMID | 24058414 |
| Title | Knockdown of human TCF4 affects multiple signaling pathways involved in cell survival, epithelial to mesenchymal transition and neuronal differentiation. |
| Abstract | Haploinsufficiency of TCF4 causes Pitt-Hopkins syndrome (PTHS): a severe form of mental retardation with phenotypic similarities to Angelman, Mowat-Wilson and Rett syndromes. Genome-wide association studies have also found that common variants in TCF4 are associated with an increased risk of schizophrenia. Although TCF4 is transcription factor, little is known about TCF4-regulated processes in the brain. In this study we used genome-wide expression profiling to determine the effects of acute TCF4 knockdown on gene expression in SH-SY5Y neuroblastoma cells. We identified 1204 gene expression changes (494 upregulated, 710 downregulated) in TCF4 knockdown cells. Pathway and enrichment analysis on the differentially expressed genes in TCF4-knockdown cells identified an over-representation of genes involved in TGF-? signaling, epithelial to mesenchymal transition (EMT) and apoptosis. Among the most significantly differentially expressed genes were the EMT regulators, SNAI2 and DEC1 and the proneural genes, NEUROG2 and ASCL1. Altered expression of several mental retardation genes such as UBE3A (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) and MEF2C was also found in TCF4-depleted cells. These data suggest that TCF4 regulates a number of convergent signaling pathways involved in cell differentiation and survival in addition to a subset of clinically important mental retardation genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | J. Biol. Chem. 2016 May -1: -1 |
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| PMID | 27137935 |
| Title | Conversion of Fibroblasts to Parvalbumin Neurons by one Transcription Factor, Ascl1, and the Chemical Compound Forskolin. |
| Abstract | Abnormalities in parvalbumin (PV)-expressing interneurons cause neurodevelopmental disorders such as epilepsy, autism, and schizophrenia. Unlike other types of neurons that can be efficiently differentiated from pluripotent stem cells, PV neurons were minimally generated using a conventional differentiation strategy. In this study, we developed an adenovirus-based transdifferentiation strategy that incorporates an additional chemical compound for the efficient generation of induced PV (iPV) neurons. The chemical compound forskolin combined with ASCL1 induced approximately 80% of mouse fibroblasts to iPV neurons. The iPV neurons generated by this procedure matured 5-7 days post infection and were characterized by electrophysiological properties and known neuronal markers, such as PV and GABA. Our studies therefore identified an efficient approach for generating PV neurons. |
| SCZ Keywords | schizophrenia, schizophrenic |