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Gene expression profiling reveals distinct cocaine-responsive genes in human fetal CNS cell types.

ABSTRACT: OBJECTIVES:Prenatal exposure to cocaine causes cytoarchitectural alterations in the developing neocortex. Previously, we reported that cocaine inhibits neural progenitor cell proliferation through oxidative endoplasmic reticulum stress and consequent down-regulation of cyclin A, whereas cyclin A expression was increased in astrocytes. In the present study, cell type-specific responses to cocaine were further explored. METHODS:Gene expression profiles were examined in five types of cells obtained from the human fetal cerebral cortex at 20 weeks gestation. Cells were treated with 100 µM cocaine in vitro for 24 hr, followed by gene expression analysis using a human neural/stem cell/drug abuse-focused cDNA array, with verification by quantitative real-time RT-PCR. RESULTS:Cocaine influenced transcription of distinct categories of genes in a cell type-specific manner. Cocaine down-regulated cytoskeleton-related genes including ezrin, ?2 actin, ?3d tubulin and ?8 tubulin in neural and/or A2B5+ progenitor cells. In contrast, cocaine modulated immune and cell death-related genes in microglia and astrocytes. In microglia, cocaine up-regulated the immunoregulatory and pro-apoptotic genes IL-1? and BAX. In astrocytes, cocaine down-regulated the immune response gene glucocorticoid receptor and up-regulated the anti-apoptotic genes 14-3-3 ? and HVEM. Therefore, cell types comprising the developing neocortex show differential responses to cocaine. CONCLUSIONS:These data suggest that cocaine causes cytoskeletal abnormalities leading to disturbances in neural differentiation and migration in progenitor cells, while altering immune and apoptotic responses in glia. Understanding the mechanisms of cocaine's effects on human CNS cells may help in the development of therapeutic strategies to prevent or ameliorate cocaine-induced impairments in fetal brain development.

SUBMITTER: Lee CT

PROVIDER: S-EPMC2952961 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Gene expression profiling reveals distinct cocaine-responsive genes in human fetal CNS cell types.

Lee Chun-Ting CT Lehrmann Elin E Hayashi Teruo T Amable Rose R Tsai Shang-Yi SY Chen Jia J Sanchez Joseph F JF Shen James J Becker Kevin G KG Freed William J WJ

Journal of addiction medicine 20091201 4

<h4>Objectives</h4>Prenatal exposure to cocaine causes cytoarchitectural alterations in the developing neocortex. Previously, we reported that cocaine inhibits neural progenitor cell proliferation through oxidative endoplasmic reticulum stress and consequent down-regulation of cyclin A, whereas cyclin A expression was increased in astrocytes. In the present study, cell type-specific responses to cocaine were further explored.<h4>Methods</h4>Gene expression profiles were examined in five types of ...[more]

PMID: 20948987

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Project description:Prion infection results in progressive neurodegeneration of the central nervous system invariably resulting in death. The pathological effects of prion diseases in the brain are morphologically well defined, such as gliosis, vacuolation, and the accumulation of disease-specific protease-resistant prion protein (PrPSc). However, the underlying molecular events that lead to the death of neurons are poorly characterised.In this study cDNA microarrays were used to profile gene expression changes in the brains of two different strains of mice infected with three strains of mouse-adapted scrapie. Extensive data was collected and analyzed, from which we identified a core group of 349 prion-related genes (PRGs) that consistently showed altered expression in mouse models. Gene ontology analysis assigned many of the up-regulated genes to functional groups associated with one of the primary neuropathological features of prion diseases, astrocytosis and gliosis; protein synthesis, inflammation, cell proliferation and lipid metabolism. Using a computational tool, Ingenuity Pathway Analysis (IPA), we were able to build networks of interacting genes from the PRG list. The regulatory cytokine TGFB1, involved in modulating the inflammatory response, was identified as the outstanding interaction partner for many of the PRGs. The majority of genes expressed in neurons were down-regulated; a number of these were involved in regulatory pathways including synapse function, calcium signalling, long-term potentiation and ERK/MAPK signalling. Two down-regulated genes coding for the transcription regulators, EGR1 and CREB1, were also identified as central to interacting networks of genes; these factors are often used as markers of neuronal activity and their deregulation could be key to loss of neuronal function.These data provides a comprehensive list of genes that are consistently differentially expressed in multiple scrapie infected mouse models. Building networks of interactions between these genes provides a means to understand the complex interplay in the brain during neurodegeneration. Resolving the key regulatory and signaling events that underlie prion pathogenesis will provide targets for the design of novel therapies and the elucidation of biomarkers.

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Dataset Information

Gene expression profiling reveals distinct cocaine-responsive genes in human fetal CNS cell types.

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Gene expression profiling reveals distinct cocaine-responsive genes in human fetal CNS cell types.

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