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Identification of a neuronal gene expression signature: role of cell cycle arrest in murine neuronal differentiation in vitro.

ABSTRACT: Stem cells are a potential key strategy for treating neurodegenerative diseases in which the generation of new neurons is critical. A better understanding of the characteristics and molecular properties of neural stem cells (NSCs) and differentiated neurons can help with assessing neuronal maturity and, possibly, in devising better therapeutic strategies. We have performed an in-depth gene expression profiling study of murine NSCs and primary neurons derived from embryonic mouse brains. Microarray analysis revealed a neuron-specific gene expression signature that distinguishes primary neurons from NSCs, with elevated levels of transcripts involved in neuronal functions, such as neurite development and axon guidance in primary neurons and decreased levels of multiple cytokine transcripts. Among the differentially expressed genes, we found a statistically significant enrichment of genes in the ephrin, neurotrophin, CDK5, and actin pathways, which control multiple neuronal-specific functions. We then artificially blocked the cell cycle of NSCs with mitomycin C (MMC) and examined cellular morphology and gene expression signatures. Although these MMC-treated NSCs displayed a neuronal morphology and expressed some neuronal differentiation marker genes, their gene expression patterns were very different from primary neurons. We conclude that 1) fully differentiated mouse primary neurons display a specific neuronal gene expression signature; 2) cell cycle block at the S phase in NSCs with MMC does not induce the formation of fully differentiated neurons; 3) cytokines change their expression pattern during differentiation of NSCs into neurons; and 4) signaling pathways of ephrin, neurotrophin, CDK5, and actin, related to major neuronal features, are dynamically enriched in genes showing changes in expression level.

SUBMITTER: Felfly H

PROVIDER: S-EPMC3174756 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Identification of a neuronal gene expression signature: role of cell cycle arrest in murine neuronal differentiation in vitro.

Felfly Hady H Xue Jin J Zambon Alexander C AC Muotri Alysson A Zhou Dan D Haddad Gabriel G GG

American journal of physiology. Regulatory, integrative and comparative physiology 20110615 3

Stem cells are a potential key strategy for treating neurodegenerative diseases in which the generation of new neurons is critical. A better understanding of the characteristics and molecular properties of neural stem cells (NSCs) and differentiated neurons can help with assessing neuronal maturity and, possibly, in devising better therapeutic strategies. We have performed an in-depth gene expression profiling study of murine NSCs and primary neurons derived from embryonic mouse brains. Microarr ...[more]

PMID: 21677276

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Project description:Stem cells are a potential key strategy for treating neurodegenerative diseases in which the generation of new neurons is critical. A better understanding of the characteristics and molecular properties of neural stem cells (NSC) and differentiated neurons can help in assessing neuronal maturity and possibly in devising better therapeutic strategies. We have therefore performed an in-depth gene expression profiling study of the C17.2 NSC line and primary neurons (PN) derived from embryonic mouse brains. Microarray analysis revealed a neuron-specific gene expression signature that distinguishes PN from NSCs, with elevated levels of transcripts involved in neuronal functions such as neurite development, axon guidance, in PN. The same comparison revealed decreased levels of multiple cytokine transcripts such as IFN, TNF, TGF, and IL. Among the differentially expressed genes, we found a statistically significant enrichment of genes in the ephrin, neurotrophin, CDK5 and actin pathways which control multiple neuronal-specific functions. Furthermore, genes involved in cell cycle were among the most significantly changed in PN. In order to better understand the role of cell cycle arrest in mediating NSCs differentiation, we blocked the cell cycle of NSCs with Mitomycin C (MMC) and examined cellular morphology and gene expression signatures. Although these MMC-treated NSCs displayed a neuronal morphology and expressed some neuronal differentiation marker genes, their gene expression patterns was very different from primary neurons. We conclude that: 1) Fully differentiated primary neurons display a specific neuronal gene expression signature; 2) cell-cycle block in NSC does not induce the formation of fully differentiated neurons; 3) Cytokines such as IFN, TNF, TGF and IL are part of normal NSC function and/or physiology; 4) Signaling pathways of ephrin, neurotrophin, CDK5 and actin, related to major neuronal features, are dynamically enriched in genes showing changes in expression level. Gene expression profiles in neuronal stem cell, mitomycin-treated neuronal stem cells and primary neuronal cultures were compared to examine cellular morphology and gene expression signatures during neuronal differentiation.

Project description:UnlabelledMany viruses replicate most efficiently in specific phases of the cell cycle, establishing or exploiting favorable conditions for viral replication, although little is known about the relationship between caliciviruses and the cell cycle. Microarray and Western blot analysis of murine norovirus 1 (MNV-1)-infected cells showed changes in cyclin transcript and protein levels indicative of a G1 phase arrest. Cell cycle analysis confirmed that MNV-1 infection caused a prolonging of the G1 phase and an accumulation of cells in the G0/G1 phase. The accumulation in G0/G1 phase was caused by a reduction in cell cycle progression through the G1/S restriction point, with MNV-1-infected cells released from a G1 arrest showing reduced cell cycle progression compared to mock-infected cells. MNV-1 replication was compared in populations of cells synchronized into specific cell cycle phases and in asynchronously growing cells. Cells actively progressing through the G1 phase had a 2-fold or higher increase in virus progeny and capsid protein expression over cells in other phases of the cell cycle or in unsynchronized populations. These findings suggest that MNV-1 infection leads to prolonging of the G1 phase and a reduction in S phase entry in host cells, establishing favorable conditions for viral protein production and viral replication. There is limited information on the interactions between noroviruses and the cell cycle, and this observation of increased replication in the G1 phase may be representative of other members of the Caliciviridae.ImportanceNoroviruses have proven recalcitrant to growth in cell culture, limiting our understanding of the interaction between these viruses and the infected cell. In this study, we used the cell-culturable MNV-1 to show that infection of murine macrophages affects the G1/S cell cycle phase transition, leading to an arrest in cell cycle progression and an accumulation of cells in the G0/G1 phase. Furthermore, we show that MNV replication is enhanced in the G1 phase compared to other stages of the cell cycle. Manipulating the cell cycle or adapting to cell cycle responses of the host cell is a mechanism to enhance virus replication. To the best of our knowledge, this is the first report of a norovirus interacting with the host cell cycle and exploiting the favorable conditions of the G0/G1 phase for RNA virus replication.

Dataset Information

Identification of a neuronal gene expression signature: role of cell cycle arrest in murine neuronal differentiation in vitro.

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Identification of a neuronal gene expression signature: role of cell cycle arrest in murine neuronal differentiation in vitro.

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